Table 1.

Recent disease modifying osteoarthritis drug trials, including category, drug class, drug name, and description of results. NCT numbers of clinical trials are included where relevant. TNF = tumor necrosis factor, WOMAC = Western Ontario & McMaster Universities Osteoarthritis index, IL = interleukin, MDM2 = mouse double minute 2 homolog, MMP = matrix metalloproteinase, ADAMTS = a disintegrin and metalloproteinase with thrombospondin motifs, MEPE = matrix extracellular phosphoglucoprotein, RANKL = receptor activator of nuclear factor kappa-B ligand, BMP = bone morphogenetic protein

Category	Drug class	Drug	Description
Anti-inflammatory	TNF-α inhibitors	Adalimumab	Randomized open-label study showed it was effective and well tolerated [11]. Randomized double-blind placebo-controlled trial showed no difference in pain or synovitis in hand OA [12].
		Infliximab	One phase IV trial showed improved WOMAC scores [13]. No new studies or trials published since then.
		DLX105 single-chain scFV antibody fragment against TNF-α	Phase I clinical trial completed in 2010 (NCT00819572), results not published.
	IL-6 receptor inhibitor	Tocilizumab	Early studies show improved pain and morning stiffness [14]. Phase 3 clinical trial completed in February 2019, awaiting results (NCT02477059).
	IL-1 inhibitor	Gevokizumab (anti-IL-1β)	Results from phase II studies in erosive hand OA did not show a greater improvement than placebo (NCT02293564, NCT01882491, and NCT01683396).
		Canakinumab (anti-IL-1β)	CANTOS study showed fewer reports of OA with canakinumab than placebo [15]. Subanalysis showed a reduced number of total knee and hip replacements in the treatment groups than in the placebo group [16]. No new trials registered to date.
		Lutikizumab (anti-IL-1α/β)	Phase II study showed limited improvement of pain and lack of synovitis improvement [17].
	IL-1Ra inhibitor	Sc-rAAV2.5IL-1Ra	Trial to started recruiting in March 2019 (NCT02790723).
	p38 inhibitor	ARRY-371797	Phase II trial completed in 2012, but no results published (NCT01366014). No further trials conducted.
	Wnt inhibitor	SM04690	Pre-clinical studies showed anti-inflammatory and cartilage protecting effects [18–20]. Results from a phase II study showed significant symptomatic improvements and increase in joint space width [21]. Different further clinical trials are ongoing (NCT03727022 and NCT03706521).
	IκB kinase inhibitor	SAR113945	Phase I trial show promising results but larger patient sample is needed to show efficacy [22]. Phase II study completed but no results published to date (NCT01598415).
Senescence	p53/MDM2 inhibitor	UBX0101	Phase I trial in patients with knee OA due for completion in 2019 (NCT03513016).
Inhibition of cartilage-degrading factors	MMP-inhibitors	Doxycycline (non-specific inhibitor)	Randomized, placebo-controlled, double-blind phase III trial showed doxycycline slowing down joint space narrowing in the index knee [23]. However, a triple-blinded randomized controlled trial did not show any reduction in symptoms but did show an increase in adverse effects [24].
	ADAMTS-inhibitors	Anti-ADAMTS-5 nanobody	Currently awaiting results from phase I clinical trial (NCT03224702) after in vitro studies showed protection against cartilage breakdown [25]. Phase I clinical trial of multiple ascending doses of anti-ADAMTS-5 nanobody in knee OA, due for completion in May 2019 (NCT03583346).
	Anti-protease	Alpha-2-macroglobulin	Phase I trial to look at the reduction of pro-inflammatory synovial fluid biomarkers in OA due for completion in 2019 (NCT03656575).
	Cathepsin K inhibitor	MIV-711	MIV-711 was well tolerated in a phase I study in healthy subjects [26]. Phase IIa trial showed significant reductions in bone and cartilage disease progression in the femur [27]. No further studies registered to date.
Promotion of cartilage building factors	Fibroblast growth factor (FGF)	Sprifermin (rhFGF-18)	After positive results in pre-clinical trials [28, 29], the results from the first-in-human clinical trial were cautiously optimistic [30]. A phase II study to further investigate safety and effectiveness is due for completion in May 2019 (NCT01919164).
	Sulfated glucosaminoglycan/precursor of glycosylated proteins	Chondroitin sulfate and glucosamine	Many clinical trials have been conducted, most of which show mixed results for chondroitin sulfate, glucosamine, as well as the two in combination [31, 32]. However, a meta-analysis has shown that chondroitin could alleviate pain and improve function and that glucosamine improved stiffness [33].
	Hyaluronic acid	Intra-articular hyaluronic acid	Meta-analysis on the effect in hip OA did not show any difference to placebo [34]. However, a meta-analysis on knee OA showed a moderate but real benefit for these patients [35]. There are many active clinical trials that compare to hyaluronic acid with placebo, PRP, or other treatments, such as NCT03852914, NCT03801564, and NCT03690232.
	MEPE derivative	TPX-100	Phase II study showed it was safe, well tolerated, and associated with significant and clinically meaningful functional benefits [36]. No further studies registered to date.
Pain	Nerve growth factor (NGF)	Tanezumab	After a successful phase I trial [37] and an earlier successful proof-of-concept study [38], now many studies in progress awaiting results.
		Falranumab	Phase II double-blind placebo-controlled trial showed positive results on pain but risk of rapid OA progression [39]. Several phase III trials were finished in 2016, but no results have come out yet.
		Fasinumab	Randomized, double-blind, placebo-controlled trial showed improvement of pain and function, while generally being well tolerated [40]. Several phase III trials are currently recruiting patients (NCT02683239, NCT03304379, and NCT03161093), as well as a trial to self-administer fasinumab (NCT03491904).
	Trans-capsaicin	CNTX-4975	Phase II revealed that a single injection improved pain with walking, knee stiffness, and physical function in OA patients with knee pain [41]. Several phase III trials (NCT03661996, NCT03660943, and NCT03429049) are currently recruiting or completing their study.
	Neurotoxic proteins	Botulinum toxin A	Phase II trials show that intra-articular injection provided pain relief and improved functional abilities in knee OA patients [42, 43]. Multiple studies are currently investigating this effect further (NCT02832713 and NCT03187626).
Repurposed drugs	RANKL inhibitor (osteoporosis)	Denosumab	Denosumab reduced early migration in total knee replacement, which often causes the need for a revision [44]. Phase II trial is currently looking at denosumab in hand OA (NCT02771860).
	Calcium-reducing hormone	Calcitonin (osteoporosis drug)	Two phase III trials did not show any clinical benefits to patients with symptomatic knee OA [45].
		Anti-calcitonin gene-related peptide (migraine drug)	Phase II study was terminated as interim assessment showed lack of efficacy [46].
	BMPs	BMP-7	Phase I trial showed a symptom response and no dose limiting toxicity [47]. However, no further studies have been done.