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] In 2021 OrthoTrophix, the developer of the drug reported that one-year study of 93 patients suggested 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] In late 2023, the company licensed TPX-100 to American Reagent in the US for an undisclosed amount. Orthotrophix

American Reagent

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] with the company claiming that the data suggested the ability to prevent cartilage loss. As of 2024, the Ember Therapeutics website is down and Google suggests that the company is permanently closed.

Ember Therapeutics [28]
FGF-18 / SpriferminPromote chondrogenesis through fibroblast growth factor receptor FGFR3 [29] Phase 2 study completed in 2017 and 5 year follow-up published in 2021, [30] demonstrated clear dose- and frequency-dependent improvements in cartilage thickness (primary endpoint), complete arrest in progression to joint replacement (in the high dose treatment groups), and improvements in the WOMAC pain survey for high-risk patients (secondary endpoint). Subsequent analysis additionally demonstrated statistically significant and clinically meaningful improvements in WOMAC progression for the high dose treatment groups relative to placebo. [31] Formation Bio

Merck Nordic Bioscience

LNA043 Chondrogenesis enhancer [32] Phase 1 study started in 2015. [33] Novartis
GLPG1972

(Proteinases Inhibitors)

 ADAMTS-5 inhibitorPhase 1 study completed in 2019.

Phase 2 study started in 2019. [34]

In October 2020, Servier reported phase 2 trial failed. [35]

Galapagos
M6495 ADAMTS-5 inhibitorPhase 1 safety study completed. [36] Novartis [37]
MIV-711

(Cathepsin K inhibitors)

 Cathepsin K inhibitor [38] Phase 2 study completed in 2019, showing prevention of cartilage damage but did not show reduction in patient pain. [39] Medivir
Invossa-K

(Transforming Growth Factor- β)

Cell/Gene therapyHuman studies halted by FDA for false ingredient claim. [40] [41] There are claims FDA allowed for phase 3 trials to resume in the US. [42] As of January 2022, phase 3 clinical trial has resumed in the US. [43] 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, [44] including BMP7.

Inflammation reducer [45] and cartilage growth enhancer. [46]

Initial 6 patient study in 2015 showed improvement in pain and function. [47] A randomised controlled trial of 200 patients completed in 2019, [48] also showing improved pain and function.

A 2019 non-randomised study in 20 patients showed improvement in joint tissue health. [49]

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. [50] [51] [52]

Paradigm Biopharmaceuticals (ASX:PAR)

Drugs under investigation

DrugMechanism of ActionStatusInvestigator(s)
A2M Protect chondrocytes from damageA2M inhibited catabolic activity in rats. [53]

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. [54]

Cytonics
SS-31 Mitoprotective peptideStudy done on 2 horses [55] showed protective effects in vivo. Cornell
TD-198946Chondrogenic factor [56] Basic science studies being carried out. University of Tokyo [57]
M6495ADAMTS-5 inhibitor [58] Shown to protect against cartilage breakdown in cartilage and synovial joint tissue explant models [59] Merck
B001-5ADAMTS-5 and ADAM-17 inhibitor [60] To be submitted to FDA in early 2020. [60] 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 osteoarthritis 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. [61]

Related Research Articles

<span class="mw-page-title-main">Cartilage</span> Resilient and smooth elastic tissue present in animals

Cartilage is a resilient and smooth type of connective tissue. It is a semi-transparent and non-porous type of tissue. It is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans, but also in cyclostomes, it may constitute a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin. It usually grows quicker than bone.

<span class="mw-page-title-main">Rose hip</span> Fruit of the rose plant

The rose hip or rosehip, also called rose haw and rose hep, is the accessory fruit of the various species of rose plant. It is typically red to orange, but ranges from dark purple to black in some species. Rose hips begin to form after pollination of flowers in spring or early summer, and ripen in late summer through autumn.

<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. It is believed to be the fourth leading cause of disability in the world, affecting 1 in 7 adults in the United States alone. 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.

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.

A chondroitin is a chondrin derivative.

<span class="mw-page-title-main">Hyaline cartilage</span> Type of cartilage in animals

Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and has a considerable amount of collagen. It contains no nerves or blood vessels, and its structure is relatively simple.

<span class="mw-page-title-main">Joint injection</span> Method of delivering drugs into a joint

In medicine, a joint injection is a procedure used in the treatment of inflammatory joint conditions, such as rheumatoid arthritis, psoriatic arthritis, gout, tendinitis, bursitis, Carpal Tunnel Syndrome, and occasionally osteoarthritis. A hypodermic needle is injected into the affected joint where it delivers a dose of any one of many anti-inflammatory agents, the most common of which are corticosteroids. Hyaluronic acid, because of its high viscosity, is sometimes used to replace bursa fluids. The technique may be used to also withdraw excess fluid from the joint.

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

Pentosan polysulfate, sold under the brand name Elmiron among others, is a medication used for the treatment of interstitial cystitis. It was approved for medical use in the United States in 1996.

Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.

<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.

Naproxcinod (nitronaproxen) is a nonsteroidal anti-inflammatory drug (NSAID) developed by the French pharmaceutical company NicOx. It is a derivative of naproxen with a nitroxybutyl ester to allow it to also act as a nitric oxide (NO) donor. This second mechanism of action makes naproxcinod the first in a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.

Articular cartilage repair treatment involves the repair of the surface of the articular joint's hyaline cartilage, though these solutions do not perfectly restore the articular cartilage. These treatments have been shown to have positive results for patients who have articular cartilage damage. They can provide some measure of pain relief, while slowing down the accumulation of damage, or delaying the need for joint replacement surgery.

<span class="mw-page-title-main">Licofelone</span> Analgesic and anti-inflammatory 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.

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.

A significant amount of research has been performed on glycosaminoglycans, especially glucosamine and chondroitin, for the treatment of arthritis. These compounds are commonly marketed as nutritional supplements and numerous 'soft therapeutic claims' are made about their health benefits - especially in aging populations. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are major components of cartilage, ingesting glucosamine might nourish joints, and thereby alleviate arthritis symptoms. Authoritative opinions on the actual therapeutic value of these compounds have been very mixed.

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

Post-traumatic arthritis (PTAr) 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.
  9. ↑ AKL Research and Development. "AKL Research & Development's novel osteoarthritis medicine APPA begins Phase II trial with partner Nordic Bioscience Clinical Development". www.prnewswire.com. Retrieved 2020-11-24.
  10. ↑ "Home". 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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  14. ↑ "Targeting the Wnt Pathway Fails in OA". www.medpagetoday.com. 2020-05-26. Retrieved 2021-03-22.
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  18. ↑ Kwon JY, Lee SH, Na HS, Jung K, Choi J, Cho KH, et al. (September 2018). "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. PMC   6138726 . PMID   30218055.
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  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". www.scripps.edu. Retrieved 2020-01-24.
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  33. ↑ Clinical trial number NCT02491281 for "First-in-human Single Ascending Dose Study of LNA043 in Patients Scheduled for Total Knee Replacement" at ClinicalTrials.gov
  34. ↑ 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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  50. ↑ 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.
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