Targeted therapies in osteoarthritis: a systematic review of the trials on

Best Practice & Research Clinical Rheumatology 24 (2010) 107–119

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Best Practice & Research ClinicalRheumatology

journal homepage: www.elsevierheal th.com/berh

10

Targeted therapies in osteoarthritis: a systematicreview of the trials on www.clinicaltrials.gov

Francis Berenbaum, MD, PhD, Director *

Pierre & Marie Curie University Paris VI, AP-HP Saint-Antoine Hospital, Paris, France

Keywords:systematic reviewosteoarthritistargeted therapiesbiotherapy

* Department of Rheumatology, Saint-Antoine HTel.: þ33 1 49 28 25 20; Fax: þ33 1 49 28 25 13.

E-mail address: [email protected]

1521-6942/$ – see front matter � 2009 Elsevier Ltdoi:10.1016/j.berh.2009.08.007

A systematic review of the clinical trials in osteoarthritis registeredon the public website of the Clinical Trials Data Bank at theNational Institutes of Health (NIH) has been performed. Sucha review should cover the majority of the ongoing or forthcomingtrials in the disease. This review focusses on trials designed to testsafety and/or efficacy of targeted therapies in osteoarthritis.

� 2009 Elsevier Ltd. All rights reserved.

Osteoarthritis (OA) represents a major therapeutic challenge. It is related, at least in part, to the lackof effective therapies able to alter the natural history of OA progression. Concerning the symptomaticdrugs, they are currently centred on the use of acetaminophen, a poorly effective drug, and non-steroidal anti-inflammatory drugs (NSAIDs), more effective than acetaminophen but with a higher riskprofile. Thus, as in rheumatoid arthritis or in ankylosing spondylitis, the future for better effectivesymptomatic and/or disease-modifying drugs with a better benefit/risk ratio will certainly come froma better understanding of the pathophysiology of the disease to test specific targets involved in painand in joint degradative processes [1]. In fact, although the optimum design for trials with a potentialdisease-modifying drug for OA is not yet decided among experts, several companies and institution aretesting novel synthetic or biological compounds right now.

The National Institutes of Health (NIH), through its National Library of Medicine (NLM) and with inputfrom the Food and Drug Administration (FDA) and others, developed the Clinical Trials Data Bank. The firstversion of the Clinical Trials Data Bank was made available to the public on 29 February 2000, on theInternet (www.clinicaltrials.gov). The website www.ClinicalTrials.gov facilitates registration of trials inaccordance with the International Committee of Medical Journal Editors (ICMJE) initiative requiring priorentry of clinical trials in a public registryas a condition for publication. Therefore, a systematic review of theclinical trials registered in this database should cover the majority of the ongoing or forthcoming trials ina pre-defined disease. This review focusses on trials registered on www.clinicaltrials.gov for treating OA.

ospital, 184 rue du faubourg Saint-Antoine, 75012 Paris, France.

d. All rights reserved.

http://www.clinicaltrials.gov

http://www.ClinicalTrials.gov


mailto:[email protected]

www.sciencedirect.com/science/journal/15216942

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744 potential relevant studies(search term : « osteoarthritis »)

33 studies with a targetedtherapy

444 non-pharmacological trials

300 trials with a pharmacological drug

267 non-targeted therapies

Fig. 1. Search results and selection of studies for systematic review.

F. Berenbaum / Best Practice & Research Clinical Rheumatology 24 (2010) 107–119108

Methodology

An exclusive search on www.clinicaltrials.gov using the single search term ‘‘osteoarthritis’’ wasperformed. The study list was screened and those studies that fit with the definition of a targetedtherapy were included. The usual definition of a targeted therapy is a specifically designed treatment tointerfere with a specific point in the pathogenesis of a disease. By this way, behavioural interventions,NSAIDs, acetaminophen, tramadol, opioids, nutraceuticals and antidepressants were excluded. Inaddition, it was decided to exclude devices, procedures and cell therapies in order to focus this analysison the pharmaceutical compounds. Registered but terminated studies before inclusion were notanalysed.

Results

The flow diagram about the results of search and their inclusion for the review are shown in Fig. 1.As on 5 August 2009, a total of 744 potential studies were identified. Studies were excluded because ofa non-pharmacological approach and 267 more studies were also excluded because they did not fitwith the definition of a targeted therapy. Of the remaining studies, 33 trials corresponded to theinclusion/exclusion criteria.

1- Targeted symptomatic drugs (Table 1)

Target Drug Mechanism of action Phase NCT Sponsor

NGF Tanezumab(RN624/PF-04383119)

Monoclonal Abanti-NGF

II 00669409 PfizerIII 00863772

00809783007339020074447100830063008633040086409700809354

PG110 Fully humanizedmonoclonal Abanti-NGF

I 00941746 PanGenetics UK Limited

(continued on next page)


Table 1 (continued)


Cannabinoidreceptor-2

GW842166 Non cannabinoidCB2 agonist

II 00479427 Glaxo-Wellcome

iGluR5 LY545694 Synthetic iGluR5antagonist

II 00790790 Eli Lilly

TRPV1 ALGRX-4975 TRPV1 agonist II 00667654 AlgoRx PharmaceuticalsBradykinin

B2 receptorIcatibant B2-kinin receptor

antagonistII 00303056 Sanofi Aventis

F. Berenbaum / Best Practice & Research Clinical Rheumatology 24 (2010) 107–119 109

1-a NGF (Nerve Growth Factor)

- Description of the target. Nerve growth factor (NGF) is the founding member of the neurotrophinfamily of structurally related secreted proteins that includes brain-derived neurotrophic factor(BDNF), neurotrophin 3 (NT-3) and NT-4. Mature neurotrophins bind to two types of receptors:a common receptor, p75NTR, which binds all neurotrophins with a similar affinity, and members ofthe trk family of receptor tyrosine kinases, trkA, trkB and trkC, which bind different neurotrophins.TrkA is the receptor tyrosine kinase for NGF [2]. NGF levels are elevated in several painful conditionsin humans, including arthritis. Administration of NGF provokes pain and hyperalgesia after local orsystemic administration. Inhibition of NGF function reduces pain and hyperalgesia in several animalmodels [3].- Tanezumab (RN624/PF-04383119) (RINAT Neurosciences, Pfizer)Description of the drug: Tanezumab is a monoclonal antibody raised against NGF.

Phase II studies:NCT00669409

This is a randomised, placebo-controlled, double-blind, dose-escalation, multicentre study of thesafety, tolerability, efficacy and pharmacokinetics of a single intravenous dose of PF-04383119 (10, 25,50, 100 and 200 mcg kg�1) in Japanese patients with moderate-to-severe pain from OA of the knee. Theprimary outcome measures are safety assessments, Western Ontario and McMaster UniversitiesOsteoarthritis index (WOMAC), visual analogue scale (VAS) for index knee pain during walking in thepast 24 h, VAS for index knee pain in the past 24 h and VAS for current index knee pain at 120 days.

Phase III studies:NCT00863772

This is a randomised, double-blind, placebo-controlled multicentre study of tanezumab (5 and10 mg every 8 weeks for 6 months, on peripheral nerve function in patients with knee OA. The primaryoutcome measure is the change from baseline in the composite measure (5NC, the mean sum score offive attributes of nerve conductionþHRdb, the measurement of heart rate variation during forcedbreathing).

NCT00809783This is a multicentre, randomised, long-term study of the safety of tanezumab (2.5, 5 or 10 mg) in

patients with OA of the knee or hip. The primary outcome measures are haematology, electrocardio-gram, clinical chemistry and adverse events during 1 year.

NCT00733902This is a 16-week randomised, double blind, placebo-controlled, multicentre study of the anal-

gesic efficacy and safety of tanezumab (IV tanezumab 2.5, 5 or 10 mg at one dose every 8 weeks) inpatients with OA of the knee. The primary outcome measures are WOMAC function and WOMACpain at week 16.

NCT00744471This is a 16-week randomised, double blind, placebo-controlled, multicentre study of the analgesic

efficacy and safety of tanezumab (IV tanezumab 2.5, 5 or 10 mg at one dose every 8 weeks) in patients


with OA of the hip. The primary outcome measures are WOMAC function, patient global assessment ofarthritis and WOMAC pain at week 16.

NCT00830063This is a 16-week randomised, double-blind, placebo- and naproxen (1 g daily)-controlled multi-

centre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 5 or 10 mg one dose atweek 0 and 8) in patients with OA of the knee. The primary outcome measures are WOMAC function,patient global assessment of arthritis and WOMAC pain at week 12 and week 16.

NCT00863304This is a 16-week randomised, double-blind, placebo- and naproxen (g daily)-controlled multi-

centre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 2.5, 5 or 10 mg every 8weeks through week 16) in patients with OA of the hip. The primary outcome measures are WOMACfunction, patient global assessment of arthritis and WOMAC pain at week 12 and week 16.

NCT00864097This is a 24-week randomised, double-blind, controlled, multicentre study of the analgesic efficacy

and safety of tanezumab (IV tanezumab 5 or 10 mg one dose at week 0 and 8) added on to diclofenac SR(75 mg BID through week 32) in patients with OA of the knee or hip. The primary outcome measuresare WOMAC function, patient global assessment of arthritis and WOMAC pain at week 24.

NCT00809354This is a 1-year multicentre, randomised, double-blind, controlled study of the long-term analgesic

efficacy and safety of tanezumab alone (IV tanezumab 5 or 10 mg every 8 weeks (through week 48)) orin combination with non-steroidal anti-inflammatory drugs (NSAIDs) (oral naproxen 500 mg BID for56 weeks or oral celecoxib 100 mg BID for 56 weeks) versus NSAIDs alone in patients with OA of theknee or hip. The primary outcome measures are WOMAC function, patient global assessment ofarthritis and WOMAC pain at week 16.

- PG110 (PanGenetics UK Limited)Description of the drug: PG110 is a fully humanised anti-NGF monoclonal antibody. It prevents theinteraction of NGF with its receptors, the high-affinity receptor TrKA and the low affinity receptor p75.PG110 does not cross-react with other neurotrophins and exerts its inhibiting activity at lower thanequimolar ratios with respect to NGF.

Phase I study:NCT00941746

This is a randomised, double-blind, placebo-controlled, single ascending dose study to evaluate thesafety, tolerability and pharmacokinetics of PG110 in patients with pain attributed to OA of the knee.The primary outcome measure is the number and severity of adverse events. The result of this study,which will be double-blind, placebo controlled, are expected in mid-2010.

1-b Cannabinoid receptor-2 (CB2)

- Description of the target. Cannabinoid receptors CB1 and CB2 belong to the family of G-protein-coupled receptors, and bind exogenous ligands derived from Cannabis sativa as well as endogenousarachidonic-derived ligands (endocannabinoids). CB2 receptors are primarily expressed in cells of theimmune system, including macrophages, and regulate the inflammatory response in various settings.CB2-selective agonists display antinociceptive activity in well-validated models of acute pain, persis-tent inflammatory pain, postoperative pain, cancer pain and neuropathic pain [4,5].

- GW842166 (Glaxo-Wellcome)Description of the drug: GW842166 is a non-cannabinoid CB2 agonist.


Phase II study:NCT00479427

This is a double-blind, two-period, placebo-controlled cross-over to evaluate the efficacy and thesafety of GW842166 in knee OA patients in a Phase IIa study. The primary outcome measure is the changein pain scores from baseline to the end of treatment using WOMAC on the pain subscore for 6–8 weeks.

1-c iGluR5 antagonists

- Description of the target. A variety of studies has indicated the involvement of kainate receptors innociception. Kainate receptors are constituted by the low-affinity iGluR5, iGluR6 and iGluR7 and thehigh-affinity KA1 and KA2 subunits, which form different homomeric or heteromeric assemblies,giving rise to functional receptors [6].

- LY 545694 (Eli Lilly)Description of the drug: Ly 545694 is a synthetic iGluR5 antagonist.


This is a randomised, double-blind, placebo-controlled study of the effects of LY545694 in thetreatment of subjects with OA knee pain. The primary outcome measure is the 24-h average pain score,weekly mean from electronic diary from baseline through 5 weeks.

1-d TRPV1 agonists

- Description of the target. The transient receptor potential (TRP) superfamily of ion channels comprisesproteins with six transmembrane domains and cytoplasmic N- and C-termini. TRP proteins assemble ashomo- or heterotetramers to form cation-permeable ion channels [7]. Currently, 28 TRP channelshave been discovered in mammals, and, based on their sequence homology, are classified intosix subfamilies: TRPC, TRPV, TRPM, TRPA, TRPP and TRPML. The vanilloid receptor TRPV1 is a homo-tetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibres). TRPV1 isthe obligate receptor for capsaicin, the spicy ingredient in hot chilli peppers [8]. TRPV1 is considered asa highly validated pain target because (i) its agonists such as capsaicin cause desensitisation of TRPV1channels that relieves pain behaviours in preclinical species and ii) its antagonists relieve painbehaviours in rodent models of inflammation, OA and cancer. Hence, both agonists and antagonists ofTRPV1 are being evaluated as potential analgesics in clinical trials.

- ALGRX-4975 (AlgoRx Pharmaceuticals)Description of the drug: ALGRX-4975 (Adlea*) is a highly purified form of capsaicin (derived from chillipeppers) that acts on TRPV-1 receptors. Adlea* acts as a TRPV-1 agonist to these pain receptors.Importantly, after initial stimulation, desensitisation of the TRPV-1 receptors blocks noxious pain withno effect on adaptive pain or position sense. This leads to a prolonged, reversible and localiseddesensitisation of the pain fibres. The drug generally has a short half-life of 1–2 h when absorbed intothe blood stream, and is undetectable in the blood after 24 h.

A single intra-articular injection of 4975 (dose range: 5 ml of 0.002, 0.02 and 0.06 mg ml�1) inpatients with end-stage OA of the knee, waiting for knee replacement, revealed no safety concerns andshowed a non-statistically significant decrease in VAS pain scores [9]. Further, in a second trial inpatients with end-stage OA of the knee waiting for knee replacement, a single intra-articular injectionof ALGRX-4975 (0.5 ml of 0.2 mg ml�1) lowered pain scores.


This is an open-label study to evaluate safety and tolerability and to explore the efficacy of dosingregimens of intra-articular 4975 in patients with chronic moderate-to-severe pain of the knee


associated with OA. The primary outcome measure is the evaluation of pain on a numerical rating scaleat prescribed times within 2 weeks. This study has been completed.

1-e Bradykinin B2 receptor antagonists

- Description of the target. Kinins are peptidic mediators that are involved in a series of pathophysio-logical processes. Bradykinin (BK) is known to have potent pro-inflammatory effects and is one of themost potent endogenous algogenic peptides. BK is formed in plasma and inflamed tissues and, byactivating the G-protein-coupled receptor, B2 receptor, present in the membrane of several cell types,initiates many processes such as vasodilation, plasma extravasation, activation of immune cells,induction of leucocyte chemotaxis and activation of nociceptive neurons. Compelling evidence hasshown that BK participates in a number of hyperalgesic and inflammatory preclinical models [10].Elevated BK levels have been demonstrated in the synovial fluid of patients with OA.

- Icatibant (Sanofi-Aventis)Description of the drug: Icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) is a potent B2-kininreceptor antagonist that blocks the vasodilatation and the increased vascular permeability associatedwith exogenous bradykinin administration both in experimental models and in vivo in man.


This is a randomised, double-blind, placebo-controlled, safety/efficacy, 13-week, multicentre studyof intra-articular multiple doses of 500 mg icatibant including 40 mg triamcinolone as calibrator inpatients with symptomatic knee OA. The primary outcome measure is pain during activity, at rest andat night measured daily through an electronic patient diary using a 100-unitVAS.

2- Targeted structure modifying drugs (Table 2)


MMPs AGG-523 Aggrecanase 1/2 inhibitor II 00454298 WyethiNOS SD-6010 Synthetic inhibitor

of iNOS activityII/III 00565812 Pfizer

Cathepsin K balicatib Inhibitor of cathepsinK activity

II 00371670 Novartis

Osteogenicprotein-1

Osteogenicprotein-1

Recombinant protein I 00456157 Stryker Biotech

FGF-18 AS902330 Human recombinant FGF-18 I 0000911469 EMD SeronoCalcitonin SMC021 Oral salmon calcitonin I 0000486369 Nordic Bioscience

& Novartis

III 0048643400704847

Vitamin D Cholecalciferol Cholecalciferol II 00306774 NIAMSIV 00599807 University of Zurich

2-1 Targeted MMP inhibitors

- Description of the target. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinasesinvolved in the degradation and remodelling of extracellular matrix proteins that are associated with thejoint degradative process. A vast number of matrix metalloproteinase inhibitors (MMPIs) have beendeveloped in recent years [11]. As MMPs have an important role in extracellular matrix (ECM) turnover,many groups have investigated if blocking MMPs will prevent tissue destruction. Early challengesinvolved the development of MMP inhibitors with high potency that would be orally available, avoidingmodification or destruction within the gut. Some of these compounds were found to cause


musculoskeletal pain and tendonitis was identified as a reversible side effect in treated patients. Suchsymptoms were seen with a compound Ro 31-9790 (Roche) and this led to its withdrawal from devel-opment as an arthritis treatment [12]. Various explanations have been offered to explain why many ofthe metalloproteinase inhibitors have been unsuccessful in clinical trials in patients with joint diseases.

- AGG-523 (Wyeth)Description of the drug: AGG-523 is an aggrecanase 1/2 inhibitor.


This is a randomised, double-blind, placebo-controlled, multiple-dose regimen study of the safety,tolerability, pharmacokinetics and pharmacodynamics of AGG-523 administered orally to subjectswith severe knee OA. The drug was taken during the 4-week period before having a total kneereplacement. This study has been completed.

2-2 iNOS inhibitor

- Description of the target. The mammalian nitric oxide synthase (NOS) enzyme family comprises threeisoforms: inducible NOS (iNOS), neuronal NOS (nNOS) and endothelial NOS (eNOS). Many studies haveindicated that iNOS induction can be evoked by various stimuli, some of which include several cyto-kines. It is a well-known fact that nitric oxide (NO) exhibits many biological functions that are involvedin vasodilation, neurotransmission, tissue homeostasis, wound repair, inflammation and cytotoxicity.Reports have identified NO as one of the pro-inflammatory mediators of arthritis in human andexperimental animal studies. Furthermore, increased concentrations of nitrite, a stable metabolite ofNO, have been observed in the serum and synovial fluid of patients with OA [13].

- SD-6010 (Pfizer)Description of the drug: SD-6010 is a synthetic inhibitor of iNOS activity.

Phase II/III study:NCT00565812

This is a long-term randomised, double-blind, placebo-controlled safety/efficacy X-ray study oforally administered SD-6010 in subjects with symptomatic OA of the knee. The primary outcomemeasure is the assessment of the progression rate of joint space narrowing in over a 24-month period.The recruitment was ongoing in July 2009.

2-3 Cathepsin K inhibitor

Description of the target. Cysteine cathepsins are a large family of proteolytic enzymes active at acidic pHas found in lysosomes. Cathepsin K (cat K), a cysteine protease, was identified initially in osteoclasts.Several recent observations have demonstrated up-regulation of cat K in osteoarthritic cartilage andinflamed synovial tissue. As cat K is one of the few extracellular proteolytic enzymes capable of degradingnative fibrillar collagen, it may play an important role in the progressive destruction of articular cartilageboth in OA and in inflammatory arthritides. Furthermore, in transgenic mice, the overexpression of cat Kresults in the spontaneous development of synovitis and cartilage degradation [14].

- Balicatib (Novartis)Description of the drug: Balicatib is a pharmacological compound, which inhibits cat K activity.


This is a 12-month, double-blind, placebo-controlled, dose-finding, multicentre study evaluating thesafety, tolerability and disease-modifying efficacy of daily oral AAE581 (10, 25 and 50 mg tablets) in patientswith painful knee OA, Kellgren-Lawrence grade 3 by X-ray. The primary outcome measure is a change frombaseline in knee cartilage volume in the target compartment after 6 months. This study has been completed.


2-4 Growth factors

a) Osteogenic protein-1

- Description of the target. Osteogenic protein-1 (OP-1) is a unique growth factor, which, unlike othermembers of the same bone morphogenetic protein (BMP) family, exhibits, in addition to its strong pro-a-nabolic activity, very prominent anti-catabolic properties. Animal studies have demonstrated that OP-1 hasthe ability to repair cartilage in vivo in various models of articular cartilage degradation, including focalosteochondral and chondral defects and OA, as well as models of degeneration in intervertebral disccartilage. Together, our findings indicate a significant promise for OP-1 as therapeutic in cartilage repair [15].

- Osteogenic protein-1 (Stryker Biotech)Description of the drug: no information found.


This is a double-blind, randomised, single-dose-escalation safety study of intra-articular osteogenicprotein-1 in subjects with OA of the knee. The primary outcome measure is the determination of thesafety and the tolerability as well as the dose-limiting toxicity (DLT) and maximal tolerated dose (MTD)of intra-articular OP-1. As of June 2009, the study has been completed.

b) FGF-18

- Description of the target. FGF-18 belongs to the fibroblast growth factor (FGF) family. It plays a centralrole in skeletal growth and development. FGFs transmit their signals through binding and activation ofone of four FGF receptor tyrosine kinases. FGF18 activates the IIIc splice variants of FGFR2 and FGFR3receptors known to play major roles in bone and cartilage biology. FGF18 has been shown to havesignificant anabolic effects on chondrocytes. Local delivery of adenovirus-expressing FGF18 into thepinnae of nude mice increased the formation of auricular cartilage expressing high levels of type IIcollagen and proteoglycans. FGF18 has been shown to stimulate the growth and proteoglycan synthesisof mature primary porcine and human articular chondrocytes and the growth of neonatal rat costalchondrocytes. FGF18-induced dose-dependent increases in cartilage thickness of the tibial plateau, dueto new cartilage formation at the articular surface and the joint periphery. The generation of newcartilage resulted in significant reductions in cartilage degeneration scores. The highest dose of FGF18also induced an increase in chondrophyte size and increased remodelling of the subchondral bone [16].

- AS902330 (EMD Serono)Description of the drug: AS902330 is the human recombinant FGF-18.


This is a randomised, double-blind, placebo-controlled, multicentre, single and multiple ascendingdose study of AS902330 (rhFGF-18) administered intra-articularly in patients with knee primary OA,who are candidates for total knee replacement. The primary outcome measures are the incidence andseverity of treatment-emergent adverse events, the proportion of subjects with predefined localadverse events, the local tolerability in the target knee and the laboratory safety parameters up to 24weeks post-treatment.

2-5 Calcitonin

- Description of the target. Calcitonin is a 32-amino-acid peptide secreted by the C cells of the thyroidin mammals. Calcitonin possesses potent antiresorptive effects, which are mediated by directbinding of calcitonin to its receptor on the osteoclasts [17]. Various sources of calcitonin are found, ofwhich salmon is the most potent. In vitro and ex vivo studies have found that calcitonin has bothanti-catabolic and anabolic effects in cartilage, by attenuating proteoglycan and collagen type II


degradation as well as by inducing their syntheses. Calcitonin could promote the synthesis ofimportant cartilage matrix such as proteoglycans and collagen II, propelling the regeneration ofcartilage and subchondral bone. In various models of cartilage degradation, the effect of calcitoninhas been demonstrated [18].

- Oral salmon Calcitonin (SMC 021, Nordic Bioscience & Novartis)Description of the drug: This drug is an association of the salmon calcitonin peptide with an oral deliveryagent, a caprylic acid derivative. This oral delivery agent uses the body’s natural passive transcellulartransport process allowing peptides to cross cell membranes without chemical modification or damageto the biological membrane. Once the peptide crosses the membrane, the delivery agent dissociatesfrom the drug and the drug re-establishes its natural distribution of conformation, ensuring that thedelivered drug is in its therapeutically active state.


This is a randomised, double-blind, placebo-controlled safety/efficacy study in patients with OA.The primary outcome measures are the assessment of the effect of different doses of oral calcitonin(0.6 mg and 0.8 mg oral) compared with placebo on serum CTX-I and CTX-II and the assessment of thetolerance profile of different doses/formulations of oral calcitonin compared with placebo up to 14days.

Phase III studies:NCT00486434

This is a randomised, double-blind, multicentre, placebo-controlled study to evaluate the efficacyand safety of oral salmon calcitonin (0.8 mg SMC021, twice daily) in the treatment of subjects withknee OA. The primary outcome measures are joint space narrowing in the medial tibiofemoral kneejoint in signal knee measured by X-ray after 12 and 24 months, pain to be assessed by WOMAC painsubscore in the signal knee and functional disability to be assessed by WOMAC function subscore in thesignal knee.

NCT00704847This is a randomised, double-blind, multicentre, placebo-controlled study to evaluate the efficacy

and safety of oral salmon calcitonin (0.8 mg, twice daily) in the treatment of subjects with knee OA. Theprimary outcome measures are joint space narrowing in the medial tibiofemoral knee joint in thesignal knee measured by X-ray after 24 months and pain to be assessed by WOMAC pain subscore inthe signal knee. The study is ongoing but not recruiting.

2-6 Vitamin D

- Description of the target. Vitamin D is either produced in the skin by exposure to UVB radiation oris ingested in the diet, and then is converted to 25-hydroxyvitamin D (25OHD) in the liver.25OHD is then taken up by renal proximal tubule epithelial cells through megalin-dependentendocytosis, and is subjected to 1alpha-hydroxylation to produce 1,25-dihydroxyvitamin D [1,25(OH) (2)D] , an active form of vitamin D. The molecule 1,25 (OH) (2)D exerts various effectsthrough nuclear vitamin D receptor (VDR) in target organs, including kidney, intestine and bone[19]. Preliminary evidence suggests that vitamin D has direct effects on chondrocytes in OAcartilage, and vitamin D receptors have been demonstrated in human articular chondrocytes ofOA cartilage. Vitamin D may also exert an effect on OA through bone, and vitamin D insuffi-ciency could impair the ability of bone to respond optimally to insults, thus predisposing todisease progression. Epidemiologic studies have shown that vitamin D deficiency was associatedwith an increased risk of progression of knee OA (both joint space narrowing (JSN) and osteo-phytes) and incidence of hip OA (JSN but not osteophytes). However, there are some contro-versies on such an association.


- CholecalciferolDescription of the drug: Cholecalciferol is the non-hydroxylated form of vitamin D3.

Phase II study:NCT00306774, NIAMS

This is a randomised, double-blind efficacy study in patients with symptomatic knee OAassigned to receive vitamin D at 2000 International Units (IU) a day or a placebo for 2 years. Theprimary outcome measures are cartilage volume loss (MRI) and knee symptoms (WOMACquestionnaire).

Phase IV study:NCT00599807, University of Zurich

This is a 2-year double-blind randomised controlled trial in 380 community-dwelling individualsage 60 years or older undergoing unilateral total knee replacement due to severe OA of the knee. Thisstudy will compare an oral dose of 2000 IU of vitamin D3 per day with 800 IU. The primary outcomemeasures are pain and disability assessed by the pain and function subscales of WOMAC related torehabilitation of the operated knee and related to the expected high prevalence of OA in the contra-lateral knee.

3- Targeted symptomatic with potential structure-modifying activities (Table 3)


IL-1 AMG108 Fully human monoclonalantibody anti-IL-1

II 00110942 Amgen

IL-1Ra IL-1 receptor antagonist II 0000110916 AmgenII 00332254 Duke University

TNFa Adalimumab Fully human monoclonalantibody anti-TNFa

II 00185562 Stanford UniversityII 00296894 University hospital of GhentII 00686439 University of AlbertaIII 00597623 Assistance Publique–hopitaux

de Paris & AbbottESBA105 Single chain (scFv) antibody

fragment against TNFaI/IIa 00819572 ESBATech AG

A3AR CF101 Oral A3AR agonist II 00837291 Can-Fite BioPharma

3-1 IL-1inhibitors

- Description of the target. Interleukin (IL)-1 is a cytokine that plays a major role in inflammatoryresponses in the context of infections and immune-mediated diseases. IL-1 is present in thesynovial fluid and in the cartilage of patients with OA. Several in vitro studies have shown that IL-1stimulates the production of mediators such as prostaglandin E(2), NO, cytokines, chemokines andadhesion molecules that are involved in articular inflammation. Furthermore, IL-1 stimulates thesynthesis and activity of MMPs and other enzymes involved in cartilage destruction in OA. Theeffects of IL-1 are inhibited in vitro and in vivo by natural inhibitors such as IL-1 receptor antag-onist and soluble receptors. The use of IL-1 inhibitors in experimental models of inflammatoryarthritis and OA has provided a strong support for the role of IL-1 in the pathogenesis of thesediseases [20].

- AMG108 (Amgen)Description of the drug: AMG108 is a fully human monoclonal antibody that targets IL-1.


Phase II:NCT00110942

This is a randomised, double-blind, placebo-controlled study evaluating the safety, tolerability,pharmacokinetics and efficacy of systemic AMG 108 (300 mg subcutaneously (SC) every 4 weeks forthree doses) in subjects with knee OA. The primary outcome measure is the change in WOMAC painscore. The study has been completed.

- IL1receptor antagonist (IL-1Ra) - (AMGEN)Description of the drug: IL-1 receptor antagonist belongs to the IL-1 family of cytokines and binds to IL-1receptors but does not induce any intracellular response. IL-1 receptor antagonist inhibits the effect ofIL-1 by blocking its interaction with cell surface receptors.


This is a randomised, double-blind, placebo-controlled study to assess the efficacy and safety ofa single intra-articular 50 mg anakinra, 150 mg anakinra or placebo injection in subjects with OA of theknee. The primary outcome measure was the change in the WOMAC score from baseline to week 4.

This study has been recently published [21]. Of the 170 patients who enrolled, 160 (94%) completedthe study. The mean improvements from baseline to week 4 in the WOMAC score were not statisticallydifferent between the placebo group and the patients who received 50 mg of anakinra (P¼ 0.67) or150 mg of anakinra (P¼ 0.77). Anakinra was well tolerated. No withdrawals due to serious adverseevents, and no serious infections or deaths were reported. No clinically significant trends were noted inlaboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminalhalf-life of anakinra in serum after intra-articular injection was approximately 4 h.

NCT00332254 (Duke University)This is a randomised, double-blind safety/efficacy study for the prevention of chondropathy following

knee injury evaluating intra-articular 150 mg IL-1Ra within 30 days of an acute knee injury that requiressurgical repair. The primary outcome measure is pain at 4 and 30 days. The study has been completed.

3-2 TNF inhibitors

- Description of the target. Tumour necrosis factor (TNF) was isolated on the basis of its ability to killtumour cells in vitro and to cause haemorrhagic necrosis of transplantable tumours in mice. TNF is oneof 10 known members of a family of ligands that activate a corresponding family of structurally relatedreceptors [22]. The important role of TNF-a in OA emerges from the fact that human articular chon-drocytes from OA cartilage expressed a significantly higher number of the p55 TNF-a receptor, whichcould make OA cartilage particularly susceptible to TNF-a degradative stimuli. In addition, OA cartilageproduces more TNF-a than normal cartilage.

- Adalimumab (ABBOTT)Description of the drug: Adalimumab is a fully human monoclonal antibody raised against TNF-a.

Phase II studies:NCT00185562 (Stanford University)

This is a non-randomised, open-label, uncontrolled, single group assignment evaluating the safety/efficacy at 12 weeks of adalimumab in subjects with active erosive inflammatory OA, who have hadan inadequate response to NSAID therapy. The primary outcome measure is safety. This study iscompleted.

NCT00296894 (University Hospital, Ghent)This is a randomised, double-blind, placebo-controlled cross-over study evaluating the efficacy of

adalimumab 40 mg SC every other week for 1 year in patients with erosive OA of the interphalangealfinger joints. The primary outcome measure is the evaluation of X-rays and of clinical parameters (pain,daily functioning, etc.). The study has been completed.


NCT00686439 (University of Alberta)This is a non-randomised, open label, uncontrolled, single-group assignment, efficacy study of

adalimumab (40 mg on alternate weeks) in inflammatory OA of the knee. The primary outcomemeasure is the OARSI/OMERACT response index at 12 weeks.

Phase III studies:NCT00597623 (Assistance Publique - Hopitaux de Paris and Abbott)

This is a randomised double-blind placebo-controlled trial of the efficacy of adalimumab (two SCinjections separated by a 2-week interval of either adalimumab or placebo) in patients with incapa-citating hand OA, refractory to usual treatment. The primary outcome measure is the level of pain onVAS 4 weeks following the last injection. The recruitment is ongoing.

- ESBA105 (ESBATech AG)Description of the drug: ESBA105 is a single-chain (scFv) antibody fragment against TNF-a.

Phase I/IIa study:NCT00819572

This is a double-blind, randomised, placebo-controlled study investigating the safety, tolerabilityand efficacy on pain of intra-articular ESBA105 applied to patients with severely painful OA of the knee.The primary outcome measures are the change from baseline (day 0) to day 7 in a 100-mm VAS toassess the intensity of knee pain and the safety assessment during the study period. The study will beconducted in two sequential parts. In a first part, four different doses of ESBA105 will be compared ina sequential, escalating scheme against placebo treatment. In the second part of the study, two doses ofESBA105, chosen based on safety data from the first part will be compared with placebo treatment. Thisstudy is currently recruiting participants.

3-3 A3AR agonist

- Description of the target. Adenosine (9-ß-d-ribofuranosyladenine), the purine nucleoside, mediatesvarious physiological cellular activities, such as cell growth, differentiation and cell death. Adenosine isreleased into the extracellular environment from activated or metabolically stimulated cells and bindsto selective G-protein-associated membrane receptors, designated.

A1, A2A, A2B and A37. The cumulative effects of activated adenosine A2 and A3 receptors (A2AR,A3AR) on mononuclear cells of the immune system are considered anti-inflammatory. Modification ofmonocyte/macrophage function by adenosine is expressed by decreased production of pro-inflam-matory cytokines, such as TNF-a, interleukin-6 (IL-6) and IL-8 and the increase of the anti-inflam-matory cytokine IL-10. A3AR was found to mediate part of the anti-inflammatory effect of adenosine.A3AR activation in macrophages and lymphocytes was shown to decrease the intracellular level ofnuclear factor-kappa B (NF-kb), leading to a decrease in the transcription of TNF-a [23].

- CF101 (Can-Fite BioPharma)Description of the drug: CF 101 is an oral A3 adenosine receptor (A3AR) agonist.


This is a multicentre, randomised, double-blind, placebo-controlled, parallel-group study of theefficacy and safety of daily CF101 (1 mg BID) administered orally for 12 weeks to patients with OA of theknee. The primary outcome measure is the proportion of responders by OMERACT-OARSI definition.

Discussion and conclusion

This systematic review gives an overview on the different targets, which have succeeded inovercoming the pre-clinical study hurdles. Many of them are now devoted to demonstrate the proof-of-concept but some are already in phase III. It is noteworthy that some of these trials involve


biotechnologies opening a new area of treatment based on biotherapies in OA. Several compoundsare focussed on pain, demonstrating the recent advances in the knowledge of pain pathways at themolecular level. For example, the first potential biotherapy in OA, monoclonal NGF antibody is in phaseIII, the proof-of-concept study in OA patients showing encouraging results [24].

As expected, a few studies aim to show a structural disease-modifying effect. Although many targetscould be tested, an absence of international consensus to design clinical trials appropriately to assesssuch an indication unfortunately slows down clinical research. However, the recent developments onthe role of the subchondral bone in the initiation and the progression of OA has persuaded somecompanies to test the efficacy of anti-osteoporotic drugs such as calcitonin. Due to the methodology ofthis review, it was not possible to include other anti-osteoporotic drugs than calcitonin or vitamin Dsuch as strontium ranelate or bisphosphonates since the ongoing trials are not registered in thedatabase.

In conclusion, instead of a pessimistic view regarding the future for the treatment of OA, thissystematic review of www.clinicaltrials.gov opens new perspectives and shows that big pharmaceu-tical companies along with biotechnology companies are in the starting block for the development ofthe next decade’s blockbusters, in aid of desperate patients.

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