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]

Contents

Approved for human use

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

Drugs with undergoing human trials

DrugMechanism of ActionStatusInvestigator(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 inhibitorPhase 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 / KartogeninInduces 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 / SpriferminPromote 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 inhibitorPhase 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 inhibitorPhase 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 therapyHuman 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

DrugMechanism of ActionStatusInvestigator(s)
A2M Protect chondrocytes from damageA2M 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 peptideStudy done on 2 horses [53] showed protective effects in vivo. Cornell
TD-198946Chondrogenic factor [54] Basic science studies being carried out. University of Tokyo [55]
M6495ADAMTS-5 inhibitor [56] Shown to protect against cartilage breakdown in cartilage and synovial joint tissue explant models [57] Merck
B001-5ADAMTS-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]

Related Research Articles

<span class="mw-page-title-main">Chondroitin sulfate</span> Sulfated glycosaminoglycan (GAG) compound

Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars. It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. Chondroitin sulfate is an important structural component of cartilage, and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis, although large clinical trials failed to demonstrate any symptomatic benefit of chondroitin.

<span class="mw-page-title-main">Osteoarthritis</span> Form of arthritis caused by degeneration of joints

Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the world. The most common symptoms are joint pain and stiffness. Usually the symptoms progress slowly over years. Other symptoms may include joint swelling, decreased range of motion, and, when the back is affected, weakness or numbness of the arms and legs. The most commonly involved joints are the two near the ends of the fingers and the joint at the base of the thumbs, the knee and hip joints, and the joints of the neck and lower back. The symptoms can interfere with work and normal daily activities. Unlike some other types of arthritis, only the joints, not internal organs, are affected.

<span class="mw-page-title-main">Celecoxib</span> Nonsteroidal anti-inflammatory drug

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of two polysaccharides, chitosan and chitin. Glucosamine is one of the most abundant monosaccharides. Produced commercially by the hydrolysis of shellfish exoskeletons or, less commonly, by fermentation of a grain such as corn or wheat, glucosamine has many names depending on country.

<span class="mw-page-title-main">Idebenone</span> Chemical compound

Idebenone is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.

<span class="mw-page-title-main">Diflunisal</span> Nonsteroidal anti-inflammatory (NSAID), Used as an analgesic & anti inflammatory

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

<span class="mw-page-title-main">Latrepirdine</span> Antihistamine drug

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<span class="mw-page-title-main">FGF18</span> Mammalian protein found in Homo sapiens

Fibroblast growth factor 18 (FGF18) is a protein that is encoded by the Fgf18 gene in humans. The protein was first discovered in 1998, when two newly-identified murine genes Fgf17 and Fgf18 were described and confirmed as being closely related by sequence homology to Fgf8. The three proteins were eventually grouped into the FGF8 subfamily, which contains several of the endocrine FGF superfamily members FGF8, FGF17, and FGF18. Subsequent studies identified FGF18's role in promoting chondrogenesis, and an apparent specific activity for the generation of the hyaline cartilage in articular joints.

<span class="mw-page-title-main">Proteoglycan 4</span> Proteoglycan; lubricant; gene

Proteoglycan 4 or lubricin is a proteoglycan that in humans is encoded by the PRG4 gene. It acts as a joint/boundary lubricant.

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<span class="mw-page-title-main">Licofelone</span> Chemical compound

Licofelone is a dual COX/LOX inhibitor that was studied in clinical trials as a treatment for osteoarthritis and which was under development by Merckle GmbH with partners Alfa Wassermann and Lacer.

<span class="mw-page-title-main">Sodium hyaluronate</span> Chemical compound

Sodium hyaluronate is the sodium salt of hyaluronic acid, a glycosaminoglycan found in various connective tissue of humans.

<span class="mw-page-title-main">Losmapimod</span> Chemical compound

Losmapimod (GW856553X) is an investigational drug being developed by Fulcrum Therapeutics for the treatment of facioscapulohumeral muscular dystrophy (FSHD); a phase III clinical trial is pending approval. Losmapimod selectively inhibits enzymes p38α/β mitogen-activated protein kinases (MAPKs), which are modulators of DUX4 expression and mediators of inflammation.

<span class="mw-page-title-main">Carfilzomib</span> Chemical compound

Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.

<span class="mw-page-title-main">ALK inhibitor</span>

ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation. They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion, although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC. For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.

Flexion Therapeutics is an American biopharmaceutical company based in Burlington, Massachusetts that is focused on the discovery, development and commercialization of novel, local therapies for the treatment of patients with musculoskeletal conditions, beginning with osteoarthritis (OA), the most common form of arthritis.

Gene therapy for osteoarthritis is the application of gene therapy to treat osteoarthritis (OA). Unlike pharmacological treatments which are administered locally or systemically as a series of interventions, gene therapy aims to establish sustained therapeutic effect after a single, local injection.

Sprifermin (INN), is a recombinant human fibroblast growth factor 18 (rhFGF18) analog, which is under development by TrialSpark for the treatment of osteoarthritis. FGF18 and sprifermin act via the Fibroblast Growth Factor Receptor (FGFR) family, with preferential activity via FGFR3c.

There is a history of clinical research done on glycosaminoglycans, especially glucosamine and chondroitin, for the treatment of arthritis. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are major components of cartilage, ingesting glucosamine might nourish joints, and thereby alleviate arthritis symptoms.

<span class="mw-page-title-main">Post-traumatic arthritis</span> Medical condition

Post-traumatic arthritis (PTA) is a form of osteoarthritis following an injury to a joint.

References

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  2. ↑ Oo WM, Little C, Duong V, Hunter DJ (2021-07-06). "The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date". Drug Design, Development and Therapy. 15: 2921–2945. doi: 10.2147/DDDT.S295224 . PMC   8273751 . PMID   34262259. S2CID   235820469.
  3. ↑ "New targets in osteoarthritis are about more than just pain". Biocentury Innovations.
  4. 1 2 Oo WM, Hunter DJ (January 2022). "Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs)". Therapeutic Advances in Musculoskeletal Disease. 14: 1759720X221090297. doi:10.1177/1759720X221090297. PMC   9128067 . PMID   35619876.
  5. ↑ "OrthoTrophix ~ TPX-100".
  6. 1 2 McGuire D, Segal N, Metyas S, Barthel H, Miller M, Rosen D, Kumagai Y (2018). "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.
  7. ↑ McGuire D, Bowes M, Brett A, Miller M, Kumugai Y (April 2020). "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. doi: 10.1016/j.joca.2020.02.062 . S2CID   218844291.
  8. ↑ "About APPA". AKL Research & Development Ltd. Retrieved 2020-11-24.
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  12. ↑ Yazici Y, McAlindon TE, Gibofsky A, Lane NE, Clauw DJ, Jones MH, et al. (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.
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  32. ↑ Clinical trial number NCT03595618 for "A Study to Assess Efficacy and Safety of GLPG1972/S201086 in Patients With Knee Osteoarthritis" at ClinicalTrials.gov
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  48. ↑ Herrero LJ, Foo SS, Sheng KC, Chen W, Forwood MR, Bucala R, Mahalingam S (August 2015). "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. doi:10.1128/JVI.00224-15. PMC   4505659 . PMID   26018160.
  49. ↑ Sampson MJ, Kabbani M, Krishnan R, Nganga M, Theodoulou A, Krishnan J (September 2017). "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. doi: 10.1186/s12891-017-1754-3 . PMC   5596862 . PMID   28899386.
  50. ↑ Stapledon CJ, Tsangari H, Solomon LB, Campbell DG, Hurtado P, Krishnan R, Atkins GJ (2019). "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. Bibcode:2019PLoSO..1422602S. doi: 10.1371/journal.pone.0222602 . PMC   6762051 . PMID   31557169.
  51. ↑ Zhang Y, Wei X, Browning S, Scuderi G, Hanna LS, Wei L (July 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 . PMC   5526282 . 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. ↑ Delco ML, Bonnevie ED, Szeto HS, Bonassar LJ, Fortier LA (February 2018). "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. PMC   6105558 . PMID   29469223.
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