Medicine:Disease-modifying osteoarthritis drug

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A disease-modifying osteoarthritis drug (DMOAD) is a disease-modifying 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.[2] 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.[3]

Approved for human use

There are currently no DMOADs approved for human use.[4]

Drugs with undergoing human trials

Drug Mechanism of Action Status Investigator(s)
TPX-100[5]

(Matrix Extracellular Phosphoglycoprotein)

23-amino acid peptide that induces articular cartilage formation [6] reduces pathological shape change of joint bones.[7] A one-year study of 93 patients revealed that TPX-100 treatment was associated with significant and sustained improvements in critical knee functions, preservation of knee cartilage thickness, reduced pathologic changes in underlying bone, and a >60% decrease in use of pain medications.[6] Orthotrophix
AKL4 / APPA[8] Oral NFkB and Nrf2 modulator National Institute for Health Research (NIHR)-approved Phase I study successfully completed 1Q 2020.

Phase 2 150-patient started 4Q 2020 with NBCD (Nordic Bioscience) and due to complete 3Q 2021.[9]

AKL Research & Development[10]
SM04690 / Lorecivivint[11] Wnt pathway inhibitor Phase 2 study completed, showing improvement in pain, function and joint space width.[12]

Phase 3 study started in May 2019.[13]

In May 2020, it was reported that phase 2a trial failed to meet primary endpoint.[14][15] But a phase 2b trial in early 2021 met primary endpoint.[16]

BioSplice(ex-Samumed) expects to release phase3 results in late 2021.[17]

Biosplice Therapeutics
KA34 / Kartogenin Induces MSCs to differentiate into chondrocytes[18] via its lytic product 4-aminobiphenyl (known as a carcinogen)[19] Phase 1 study started in May 2018 to evaluate safety of kartogenin in humans.[20] Calibr[21]
UBX0101

(Senolytic agents)

p53/MDM2 inhibitor, induces apoptosis of senescent cells to create a favourable healing environment[22] Phase 1 study complete in June 2019,[23] results were encouraging leading to plans for a phase 2 study. Phase 2 study results did not show any improvements and led to drug being discontinued from investigation.[24] Unity Biotechnology
BMP7(Bone Morphogenetic Protein 7) Supports transcription of osteogenic genes[25] Phase 1 study completed in 2010.[26]

Phase 2 study completed in 2015,[27] suggesting the ability to prevent cartilage loss.

Ember Therapeutics[28]
FGF-18 / Sprifermin Promote chondrogenesis through fibroblast growth factor receptor FGFR3[29] 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 Bioscience

LNA043 Chondrogenesis enhancer[30] Phase 1 study started in 2015.[31] Novartis
GLPG1972

(Proteinases Inhibitors)

ADAMTS-5 inhibitor Phase 1 study completed in 2019.

Phase 2 study started in 2019.[32]

In October 2020, Servier reported phase 2 trial failed.[33]

Galapagos
M6495 ADAMTS-5 inhibitor Phase 1 safety study completed.[34] Novartis[35]
MIV-711

(Cathepsin K inhibitors)

Cathepsin K inhibitor[36] Phase 2 study completed in 2019, showing prevention of cartilage damage but did not show reduction in patient pain.[37] Medivir
Invossa-K

(Transforming Growth Factor- β)

Cell/Gene therapy Human studies halted by FDA for false ingredient claim.[38][39] There are claims FDA allowed for phase 3 trials to resume in the US.[40] As of January 2022, phase 3 clinical trial has resumed in the US.[41] 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,[42] including BMP7.

Inflammation reducer[43] and cartilage growth enhancer.[44]

Initial 6 patient study in 2015 showed improvement in pain and function.[45] A randomised controlled trial of 200 patients completed in 2019,[46] also showing improved pain and function.

A 2019 non-randomised study in 20 patients showed improvement in joint tissue health.[47]

Organogenesis

Amnio Technology

MiMedx

Amniox Medical, Inc.

Polysulfate Sodium (PPS) Pentosan Polysulfate Sodium (PPS) is a semi-synthetic drug manufactured from European beech xylans that are sulfated to produce a negatively charged product that mimics glycosaminoglycans (GAGs). Paradigm's IND application to commence its phase 3 pivotal clinical trial investigating Pentosan Polysulphate Sodium (PPS) for the treatment of pain associated with knee osteoarthritis has been cleared by the US FDA.

Approximately 65 sites have been identified throughout the US and Australia. Contracting with many of those sites has been completed. The first 4 sites in Australia have initiated screening participants. Screening at the US sites is expected to begin prior to the end of CY2021.

The Company is now in a position to accelerate recruitment by adding approximately 10 sites in the United Kingdom (UK) and Europe, with site initiation and subject screening expected to commence in 1H CY 2022.[48][49][50]

Paradigm Biopharmaceuticals (ASX:PAR)

Drugs under investigation

Drug Mechanism of Action Status Investigator(s)
A2M Protect chondrocytes from damage A2M inhibited catabolic activity in rats.[51]

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.[52]

Cytonics
SS-31 Mitoprotective peptide Study done on 2 horses[53] showed protective effects in vivo. Cornell
TD-198946 Chondrogenic factor[54] Basic science studies being carried out. University of Tokyo[55]
M6495 ADAMTS-5 inhibitor[56] Shown to protect against cartilage breakdown in cartilage and synovial joint tissue explant models[57] Merck
B001-5 ADAMTS-5 and ADAM-17 inhibitor[58] To be submitted to FDA in early 2020.[58] Guangzhou Institutes of Biomedicine and Health

Gene therapy for osteoarthritis is also being investigated as technology to create a drug that would act as a disease modifying drug. Several approved drugs are being investigated as repurposed agents in the treatment of osteoarhritis such as liraglutide (anti-diabetic and anti-obesity drug: NCT02905864), Metformin (anti-diabetic drug: NCT04767841, NCT05034029), Zoledronic acid (anti-osteoporotic drug: NCT04303026), etc.[4]

Paroxetine has been deemed to have dmoad activity.[59]

References

  1. ↑ "Disease-modifying osteoarthritis drugs (DMOADs): what are they and what can we expect from them?". 2013-10-31. https://www.medicographia.com/2013/10/disease-modifying-osteoarthritis-drugs-dmoads-what-are-they-and-what-can-we-expect-from-them/. 
  2. ↑ "The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date" (in English). Drug Design, Development and Therapy 15: 2921–2945. 2021-07-06. doi:10.2147/DDDT.S295224. PMID 34262259. 
  3. ↑ "New targets in osteoarthritis are about more than just pain". Biocentury Innovations. http://ir.unitybiotechnology.com/static-files/fdcfe20f-ae3d-475d-bb88-b1e3e5293518. 
  4. ↑ 4.0 4.1 "Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs)". Therapeutic Advances in Musculoskeletal Disease 14: 1759720X221090297. January 2022. doi:10.1177/1759720X221090297. PMID 35619876. 
  5. ↑ "OrthoTrophix ~ TPX-100". http://www.orthotrophix.com/products-tpx-100.html. 
  6. ↑ 6.0 6.1 "Intra-Articular TPX-100 in Knee Osteoarthritis: Robust Functional Response at 6 and 12 Months Is Associated with Increased Tibiofemoral Cartilage Thickness". Arthritis Rheumatol. 70 (suppl 10): 3405–3406. 2018. https://acrabstracts.org/abstract/intra-articular-tpx-100-in-knee-osteoarthritis-robust-functional-response-at-6-and-12-months-is-associated-with-increased-tibiofemoral-cartilage-thickness/. 
  7. ↑ "Study TPX-100-5: Significant reduction in femoral bone shape change 12 months after IA TPX-100 correlates with tibiofemoral cartilage stabilization". Osteoarthritis and Cartilage 28: S37–S38. April 2020. doi:10.1016/j.joca.2020.02.062. https://www.oarsijournal.com/article/S1063-4584(20)30129-1/abstract/. 
  8. ↑ "About APPA" (in en-GB). https://aklrd.com/research-development/akl4/about-appa/. 
  9. ↑ AKL Research and Development. "AKL Research & Development's novel osteoarthritis medicine APPA begins Phase II trial with partner Nordic Bioscience Clinical Development" (in en). https://www.prnewswire.com/news-releases/akl-research--developments-novel-osteoarthritis-medicine-appa-begins-phase-ii-trial-with-partner-nordic-bioscience-clinical-development-301133936.html. 
  10. ↑ "Home" (in en-GB). http://www.aklrd.com/. 
  11. ↑ "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. January 2018. doi:10.1016/j.joca.2017.08.015. PMID 28888902. 
  12. ↑ "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" (in en). Osteoarthritis and Cartilage. Abstracts from the 2018 OARSI World Congress on Osteoarthritis 26: S293–S294. 2018-04-01. doi:10.1016/j.joca.2018.02.589. ISSN 1063-4584. 
  13. ↑ "Samumed Launches Phase 3 Lorecivivint (SM04690) Clinical Program in Knee Osteoarthritis". May 2, 2019. https://www.samumed.com/medium/image/samumed-launches-phase-3-lorecivivint-sm04690-clinical-program-in-knee-osteoarthritis_556/view.aspx. 
  14. ↑ "Targeting the Wnt Pathway Fails in OA" (in en). 2020-05-26. https://www.medpagetoday.com/rheumatology/arthritis/86677. 
  15. ↑ "Lorecivivint, a Novel Intraarticular CDC-like Kinase 2 and Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor and Wnt Pathway Modulator for the Treatment of Knee Osteoarthritis: A Phase II Randomized Trial". Arthritis & Rheumatology 72 (10): 1694–1706. October 2020. doi:10.1002/art.41315. PMID 32432388. 
  16. ↑ "A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis". Osteoarthritis and Cartilage 29 (5): 654–666. May 2021. doi:10.1016/j.joca.2021.02.004. PMID 33588087. 
  17. ↑ "Osman Kibar lays down his hand at Samumed, stepping away from CEO role as his once-heralded anti-aging biotech rebrands" (in en). https://endpts.com/osman-kibar-lays-down-his-hand-at-samumed-stepping-away-from-ceo-role-as-his-once-heralded-anti-aging-biotech-rebrands/. 
  18. ↑ "Kartogenin inhibits pain behavior, chondrocyte inflammation, and attenuates osteoarthritis progression in mice through induction of IL-10". Scientific Reports 8 (1): 13832. September 2018. doi:10.1038/s41598-018-32206-7. PMID 30218055. Bibcode: 2018NatSR...813832K. 
  19. ↑ "Kartogenin hydrolysis product 4-aminobiphenyl distributes to cartilage and mediates cartilage regeneration". Theranostics 9 (24): 7108–7121. 2019. doi:10.7150/thno.38182. PMID 31695756. 
  20. ↑ Clinical trial number NCT03133676 for "A Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of KA34 in Subjects With Knee Osteoarthritis" at ClinicalTrials.gov
  21. ↑ "Calibr | Scripps Research". https://www.scripps.edu/science-and-medicine/calibr/. 
  22. ↑ "Safety, Tolerability, Pharmacokinetics, and Clinical Outcomes Following Single-Dose IA Administration of UBX0101, a Senolytic MDM2/p53 Interaction Inhibitor, in Patients with Knee OA" (in en-US). https://acrabstracts.org/abstract/safety-tolerability-pharmacokinetics-and-clinical-outcomes-following-single-dose-ia-administration-of-ubx0101-a-senolytic-mdm2-p53-interaction-inhibitor-in-patients-with-knee-oa/. 
  23. ↑ "UNITY Biotechnology, Inc. Announces Plan for Phase 2 Clinical Study of UBX0101 in Osteoarthritis of the Knee" (in en). http://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-inc-announces-plan-phase-2-clinical-study. 
  24. ↑ "UNITY Biotechnology Announces 12-week data from UBX0101 Phase 2 Clinical Study in Patients with Painful Osteoarthritis of the Knee". August 17, 2020. https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-announces-12-week-data-ubx0101-phase-2/. 
  25. ↑ "Relationship of plasma and synovial fluid BMP-7 with disease severity in knee osteoarthritis patients: a pilot study". International Orthopaedics 33 (4): 1171–1175. August 2009. doi:10.1007/s00264-009-0751-z. PMID 19301001. 
  26. ↑ "Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis". BMC Musculoskeletal Disorders 11: 232. October 2010. doi:10.1186/1471-2474-11-232. PMID 20932341. 
  27. ↑ Ember Inc. Therapeutics. "Ember Therapeutics Announce Initial Positive Results From a Phase 2 Trial of BMP-7 in Patients with Moderate Osteoarthritis of the Knee" (in en). https://www.prnewswire.com/news-releases/ember-therapeutics-announce-initial-positive-results-from-a-phase-2-trial-of-bmp-7-in-patients-with-moderate-osteoarthritis-of-the-knee-300162094.html. 
  28. ↑ "Ember Therapeutics". http://www.embertx.com/. 
  29. ↑ "Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis". The Journal of Biological Chemistry 280 (21): 20509–20515. May 2005. doi:10.1074/jbc.M410148200. PMID 15781473. 
  30. ↑ "LNA043: Chondrogenesis inducer for cartilage repair". Meet Novartis Management NIBR. https://www.novartis.com/sites/www.novartis.com/files/2017-05-meet-the-management-nibr.pdf. 
  31. ↑ Clinical trial number NCT02491281 for "First-in-human Single Ascending Dose Study of LNA043 in Patients Scheduled for Total Knee Replacement" at ClinicalTrials.gov
  32. ↑ Clinical trial number NCT03595618 for "A Study to Assess Efficacy and Safety of GLPG1972/S201086 in Patients With Knee Osteoarthritis" at ClinicalTrials.gov
  33. ↑ "Galapagos and Servier report topline results for ROCCELLA Phase 2 clinical trial with GLPG1972/S201086 in knee osteoarthritis patients" (in en-US). 15 October 2020. https://servier.com/en/communique/galapagos-and-servier-report-topline-results-for-roccella-phase-2-clinical-trial-with-glpg1972-s201086-in-knee-osteoarthritis-patients/. 
  34. ↑ "Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of the Anti-ADAMTS-5 Nanobody®, M6495, in Healthy Male Subjects: A Phase I, Placebo-Controlled, First-in-Human Study" (in en-US). https://acrabstracts.org/abstract/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-single-ascending-doses-of-the-anti-adamts-5-nanobody-m6495-in-healthy-male-subjects-a-phase-i-placebo-controlled-first-in-huma/. 
  35. ↑ "Occupied with immunology and cancer, Merck KGaA hands off osteoarthritis drug to Novartis for €50M cash" (in en). https://endpts.com/occupied-with-immunology-and-cancer-merck-kgaa-hands-off-osteoarthritis-drug-to-novartis-for-e50m-cash/. 
  36. ↑ "Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial". Annals of Internal Medicine 172 (2): 86–95. January 2020. doi:10.7326/M19-0675. PMID 31887743. 
  37. ↑ Clinical trial number NCT02705625 for "A Study to Evaluate the Efficacy, Safety and Tolerability of MIV-711 in Osteoarthritis Patients" at ClinicalTrials.gov
  38. ↑ "Prosecutors seek to arrest 2 Kolon execs for false Invossa data - Korea Biomedical Review" (in ko). 2019-10-31. http://www.koreabiomed.com/news/articleView.html?idxno=6729. 
  39. ↑ "Kolon TissueGene feared to be delisted due to cancellation of Invossa approval" (in ko). 2019-05-29. http://www.koreaittimes.com/news/articleView.html?idxno=91012. 
  40. ↑ "Kolon TissueGene cleared to resume US Phase III trial for Invossa". https://www.thepharmaletter.com/article/kolon-tissuegene-cleared-to-resume-us-phase-iii-trial-for-invossa. 
  41. ↑ Clinical trial number NCT03291470 for "A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Phase 3 Study to Determine the Efficacy and Safety of TG-C in Subjects With Kellgren and Lawrence Grade 2 or 3 Osteoarthritis of the Knee" at ClinicalTrials.gov
  42. ↑ A Primer on Amniotic Membrane Regenerative Healing. Color House Graphics. 2016. pp. 60. ISBN 978-0-692-51694-2. http://www.azisks.com/wp-content/uploads/2018/03/SB300.003-A-Primer-on-Amniotic-Membrane-Regenerative-Healing.pdf. 
  43. ↑ "Amniotic Suspension Allograft Modulates Inflammation in a Rat Pain Model of Osteoarthritis". Journal of Orthopaedic Research 38 (5): 1141–1149. May 2020. doi:10.1002/jor.24559. PMID 31814175. 
  44. ↑ "Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development". Arthritis Research & Therapy 16 (1): R47. February 2014. doi:10.1186/ar4476. PMID 24499554. 
  45. ↑ "Cryopreserved Amniotic Suspension for the Treatment of Knee Osteoarthritis". The Journal of Knee Surgery 29 (6): 443–450. August 2016. doi:10.1055/s-0035-1569481. PMID 26683979. 
  46. ↑ "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. November 2019. doi:10.1055/s-0039-1696672. PMID 31533151. 
  47. ↑ "Injectable Amniotic Membrane/Umbilical Cord Particulate for Knee Osteoarthritis: A Prospective, Single-Center Pilot Study". Pain Medicine 20 (11): 2283–2291. November 2019. doi:10.1093/pm/pnz143. PMID 31418794. 
  48. ↑ "Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease". Journal of Virology 89 (15): 8063–8076. August 2015. doi:10.1128/JVI.00224-15. PMID 26018160. 
  49. ↑ "Improved clinical outcome measures of knee pain and function with concurrent resolution of subchondral Bone Marrow Edema Lesion and joint effusion in an osteoarthritic patient following Pentosan Polysulphate Sodium treatment: a case report". BMC Musculoskeletal Disorders 18 (1): 396. September 2017. doi:10.1186/s12891-017-1754-3. PMID 28899386. 
  50. ↑ "Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis". PLOS ONE 14 (9): e0222602. 2019. doi:10.1371/journal.pone.0222602. PMID 31557169. Bibcode: 2019PLoSO..1422602S. 
  51. ↑ "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. July 2017. doi:10.1186/s13075-017-1363-4. PMID 28743292. 
  52. ↑ Clinical trial number NCT03656575 for "Reduction of Pro-Inflammatory Synovial Fluid Biomarkers in Osteoarthritis of the Knee With Alpha-2 Macroglobulin" at ClinicalTrials.gov
  53. ↑ "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. February 2018. doi:10.1002/jor.23882. PMID 29469223. 
  54. ↑ "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. March 2019. doi:10.1002/term.2795. PMID 30650248. 
  55. ↑ "A novel disease-modifying osteoarthritis drug candidate targeting Runx1". Annals of the Rheumatic Diseases 72 (5): 748–753. May 2013. doi:10.1136/annrheumdis-2012-201745. PMID 23041841. 
  56. ↑ "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" (in en). Osteoarthritis and Cartilage 26: S276–S277. 2018-04-01. doi:10.1016/j.joca.2018.02.561. ISSN 1063-4584. https://www.oarsijournal.com/article/S1063-4584(18)30661-7/abstract. 
  57. ↑ "The anti-ADAMTS-5 nanobody®, M6495, protects against cartilage breakdown in cartilage and synovial joint tissue explant models" (in en). Osteoarthritis and Cartilage 26: S187. 2018-04-01. doi:10.1016/j.joca.2018.02.402. ISSN 1063-4584. https://www.oarsijournal.com/article/S1063-4584(18)30502-8/abstract. 
  58. ↑ 58.0 58.1 "The "elusive DMOAD": Aggrecanase inhibition from laboratory to clinic". Clinical and Experimental Rheumatology 37. 2019-09-17. https://www.clinexprheumatol.org/article.asp?a=14774. 
  59. ↑ "Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis". Science Translational Medicine 13 (580). February 2021. doi:10.1126/scitranslmed.aau8491. PMID 33568523. 



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