How Close are We to Having Structure-Modifying Drugs Available?

Rheum Dis Clin N Am

How Close are We to HavingStructure-Modifying Drugs Available?

David J. Hunter, MBBS, PhDa,b,*,Marie-Pierre Hellio Le Graverand-Gastineau,

MD, PhD, DScc

aDivision of Research, New England Baptist Hospital,

125 Parker Hill Ave., Boston, MA 02120, USAbBoston University School of Medicine, Boston, MA, USA

cPfizer Global Research and Development, New London, CT, USA

Osteoarthritis (OA) is a clinical condition that manifests with joint painand functional limitations. It previously was described as a cartilagecentriccondition, and the hallmark of the disease was described as cartilage loss.Although cartilage loss is a prominent feature of OA, contemporary modelsrecognize that important structural and pathologic changes also occur inother articular tissues.

More precisely, osteoarthritis can be viewed as the clinical and pathologicoutcome of a range of disorders that result in structural and functionalfailure of synovial joints with meniscal degeneration, subchondral bonealterations, bone and cartilage overgrowth (osteophytes), loss of articularcartilage, and a synovial inflammatory response [1]. OA occurs when thedynamic equilibrium between the breakdown and repair of joint tissuesbecomes unbalanced [2]. This progressive joint failure may cause pain anddisability [3], although many persons who have structural changes consistentwith OA are asymptomatic [4]. This point is particularly salient for thisarticle, because many would argue that the structural progression of this dis-ease can be altered, without regard to the symptomatic benefits. The devel-opment of agents to modify the structure of OA (disease-modifyingosteoarthritis drugs, DMOADs) needs to be viewed in this light: the currentregulatory stance appreciates that OA is a symptomatic condition, and any

34 (2008) 789–802

Dr. Hunter receives research or institutional support from AstraZeneca, DonJoy, Lilly,

Merck, National Institutes of Health, Pfizer, Stryker, and Wyeth.

* Corresponding author. Division of Research, New England Baptist Hospital, 125

Parker Hill Ave., Boston, MA 02120.

E-mail address: [email protected] (D.J. Hunter).

0889-857X/08/$ - see front matter � 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.rdc.2008.05.003 rheumatic.theclinics.com

mailto:[email protected]

http://www.rheumatic.theclinics.com

790 HUNTER & HELLIO LE GRAVERAND-GASTINEAU

improvement in structural outcome should be accompanied by a clinicalbenefit. Further, the multitude of risk factors, the complex etiopathogenesis,and the heterogeneity of clinical presentations create a complex environmentfor therapeutic development aimed at modifying structure.

This article describes what structure modification is, explains the distinc-tions among preventing, retarding, stopping, and reversing disease, and sug-gests what approaches might be clinically meaningful. It also discusseswhether any evidence suggests that it is possible to modify disease andwhether the current focus on cartilage is appropriate. It considers the meth-odologic approaches and the obstacles to demonstrating efficacy of theseagents in clinical trials. This article is a narrative review in a field that is rap-idly evolving. At the end, the authors hope the reader will appreciate thecomplexity of the field and the likely road to DMOAD development.

What is a disease-modifying osteoarthritis drug?

Primarily because OA has had such a cartilagecentric focus, the first sub-stances that protected articular cartilage during the course of destructive jointdisorders were termed ‘‘chondroprotective’’ agents because their activity wasfocusedon the chondrocyte.When the chondroprotective effect became linkedto a clinical benefit and seemed to alter the course of the disease, these agentswere termed ‘‘disease-modifying osteoarthritis drugs,’’ or ‘‘DMOADs’’ [5].

Because the typical course of OA is a slowly advancing structural pro-gression, there are a number of potential goals for these agents. In principle,one outcome of a structure-modifying trial could be that the agent wasineffective or deleterious to structure; if so, it would be unlikely to belicensed for that purpose. An example of this situation from another fieldwas the therapeutic investigation of fluoride for osteoporosis, which wasfound to increase the risk of fracture rather than reducing it [6].

Other possible outcomes of the use of DMOADs would be retardation(slowing of the rate of progression), stopping progression, reversing progres-sion (regeneration of the target tissue), or even preventing development ofthe disease. Given these possible outcomes, what effect is likely to be clini-cally meaningful? To answer that question, it is necessary to determine whatis meant by ‘‘clinically meaningful.’’ For some this term means delaying ormitigating the need for surgical intervention such as joint replacement [7].For others, it means making a meaningful impact on quality of life and inparticular physical function [8]. From a regulatory perspective, the majorlicensing authorities (the Food and Drug Administration [FDA] in theUnited States and the European Medicines Agency) have provided draftguidance documents for industry for clinical development programs foragents that modify OA structure, requiring that the agent slows joint-spacenarrowing and results in clinical benefit (eg, improvement of patient symp-toms or function). Details of the draft guidance can be found on the Internet(http://www.fda.gov/Cber/gdlns/osteo.htm).

http://www.fda.gov/Cber/gdlns/osteo.htm

791HAVING STRUCTURE-MODIFYING DRUGS AVAILABLE?

With these thresholds for detecting clinically meaningful effects, nodisease-modifying efficacy has been demonstrated convincingly for anyof the existing pharmacologic agents. Some agents have slowed structuralprogression without symptomatic benefit, suggesting that simply slowingprogression may not be sufficient to lead to symptom improvement[9,10].

Is the marriage of symptoms and structure rational?

Many would argue that slowing the rate of structural progression isa noble intent in and of itself. They also could argue that many of the tri-als of DMOADs that were interpreted as not demonstrating a clinical ben-efit suffered limitations, including a majority of patients who had little tono pain at baseline and/or the need to use concomitant standard-of-caremedications that introduced noise in the results of the symptom-assess-ment questionnaires. Given these limitations, demonstration of structuralimprovement plausibly might be dissociated from clinical benefit in thesame clinical trial. It also could be argued that the DMOAD trials inwhich structure preservation was suggested but symptoms were not af-fected did not follow participants long enough, and that the eventual clin-ical outcome might have been favorable [9,10]. Parallels may be drawnbetween the treatment of hypertension or osteoporosis, which typicallyhas no short-term symptomatic benefit but rather reduces the risk of anunfavorable long-term outcome. This approach would require that a persontake an agent for an uncertain period of time either to prevent the devel-opment of the disease (presumably before the onset of OA) or to preventthe development of symptomatic disease (in a person who has pre-existingstructural damage).

It is useful to consider this scenario in its fullest extent. Osteoarthritisaffects the majority of the population over the age of 65 years. Many believethat there is a long lead-time for the development of OA. Some data suggestthe development of OA is programmed from developmental shape [11],malalignment during adolescence [12], and/or obesity during young adultlife [13,14], suggesting that the structural failure that is OA may begin devel-oping decades before it becomes symptomatic. Thus to treat OA adequatelywith pharmacologic agents in this scenario would require treating most ofthe population for the large part of their adult lives. Given the proclivityto toxicity of most agents and the burden of expense to the health care sys-tem, this approach is not justifiable.

In an alternate scenario, a young adult sustains an tear in the anteriorcruciate ligament (ACL) or a meniscal injury that is not reparable. Thereis a high incidence of knee OA in the years following ACL [15,16] or menis-cal injury [15,17], and credible evidence suggests that current arthroscopicprocedures, including ACL reconstruction and meniscectomy, are not


sufficient to restore normal joint mechanics fully or to neutralize the long-term risk of OA [18,19]. Given the great potential for the development ofOA over a shorter time frame (7–10 years) in a more limited segment ofthe population, this alternate scenario might be possible within the presenthealth care system. Obviously this approach needs to be evaluated formally;at present it is not supported by any evidence. Potentially this approach alsocould be used if there were an algorithm that allowed the detection of thoseat greatest risk of disease based on some genetic predisposition or risk factorfor incident disease, such as obesity.

In yet another scenario, treatment might be limited to those who presentwith symptomatic disease, a much more limited segment of the population,for what presumably would be a more finite period of time. This positionalso has many fundamental limitations. Much of the current focus on agentsto modify the disease is directed at preserving hyaline articular cartilage. Inthe progression cohort of the OA Initiative, most subjects who had symp-tomatic radiographic disease seemed to have full-thickness cartilage lossover extensive areas in weight-bearing portions of the knee joint [20].Thus retarding loss in these individuals will be focused more on preservingtheir remaining cartilage. This loss seems to occur in joints that are mala-ligned, creating a harsh mechanical environment for putative agents towork in.

Further, the current FDA regulatory stance defines ‘‘structural modifi-cation’’ as imparting an effect on radiographic joint-space narrowing.Articular cartilage, however, is both aneural and avascular. As such,cartilage is incapable of generating pain, inflammation, stiffness, or anyof the symptoms that patients who have knee OA typically describe. Givenits relative unimportance to OA’s symptomatic presentation, it seemsironic that articular cartilage has received so much attention while othercommon sources of symptoms in the knee have been ignored [21]. It isimportant, however, to note that joint-space width is composed not onlyof articular cartilage but also of meniscus [22]. Unlike articular cartilage,the meniscal tissue is vascularized and innervated. In addition, althougharticular cartilage may not seem to drive symptoms directly, cartilagebreakdown may lead to the development of OA symptoms by generatingsynovial inflammation and promoting meniscal degeneration and subchon-dral bone changes in relation to changes in the biomechanical properties ofcartilage. Interventions that focus exclusively on nourishing, replenishing,or replacing articular cartilage may have little chance of providing long-term symptomatic relief unless they simultaneously relieve strain on otherinnervated structures. It is unlikely, however, that therapeutic agents affectarticular cartilage only. Several reports on degenerative changes in themeniscus in preclinical animal models of OA and in humans suggestthat the molecular pathways of tissue degeneration associated with OAin joint tissues other than cartilage are similar to and actually may precedethose occurring in the articular cartilage [23–26].


Thus both approaches have fundamental limitations, and furtherresearch is needed to understand the implications of each approach fullybefore embarking on either.

Is there evidence that suggests the disease process can be modified?

Some studies with varying levels of evidence suggest that glucosaminesulfate, chondroitin sulfate, sodium hyaluronan, doxycycline, matrix metal-loproteinase (MMP) inhibitors, bisphosphonates, calcitonin, diacerein, andavocado-soybean unsaponifiables can modify disease progression [27].

Much research effort has been directed toward identifying small-moleculeinhibitors of MMPs that act downstream in the pathophysiologic cascade.Thus far, these compounds have failed in the early clinical phase, mainly be-cause of a painful joint-stiffening tendonitis-like side effect termed ‘‘muscu-loskeletal syndrome’’ that seems to be caused by the relative broad-spectrumMMP inhibition of these compounds [28]. Some MMP inhibitors with moreselective specificity profiles are in preclinical or early clinical development.Several of these candidates are specific for MMP-13, which is overexpressedby OA cartilage, and have minimal effects on MMP-1, which has been im-plicated in the development of adverse musculoskeletal events [29].

Tetracyclines have been shown to reduce the severity of OA in animals,probably by inhibiting metalloprotease activity, and also have been studiedin early human trials with some suggestion of efficacy in slowing the progres-sion of joint-space narrowing [9]. Brandt and colleagues [9] reported thatdoxycycline slows joint-space narrowing in patients who have OA of the me-dial tibiofemoral compartment. In this placebo-controlled trial, 431 obesewomen (aged 45–64 years) who had radiographically visible unilateralknee OA were assigned randomly to receive 30 months of treatment with100 mg doxycycline or placebo twice daily. Doxycycline reduced the meanloss of joint-space width in the OA knee by approximately 30% at 30months. Doxycycline did not prevent the development of progressivejoint-space narrowing in the contralateral knee, however, and did not im-prove measures of pain or function compared with placebo. Thus, althoughdoxycycline may have had a beneficial effect on structure, the clinical mean-ingfulness of this effect remains questionable.

In a 3-year study, Dougados and colleagues [10] reported that diacereinslowed the radiographic progression of hip OA, defined by a joint-spaceloss of at least 0.5 mm. The effects were modest (54% of the patients inthe diacerein group had radiographic progression, versus 62% in the pla-cebo group) and were not associated with symptomatic improvement. A re-cent 1-year study of structural progression in knee OA failed to indicate thatdiacerein had a structure-modifying effect [30].

The strong increase in bone remodeling in OA has prompted investiga-tions of the disease-modifying potential of the bisphosphonates. Despite


promising preclinical data and observational data suggesting that antire-sorptives (alendronate and estrogen) reduce the prevalence of bone marrowlesions in the subchondral bone [31], the clinical results have been disap-pointing. In a recently conducted placebo-controlled, randomized phaseIII clinical study in patients who had knee OA, risedronate did not showany structural or symptomatic efficacy despite having salient benefits on bio-chemical markers of cartilage degradation [32] and on the architecture ofsubchondral bone [33]. The fact that the main study result was negativemay have reflected study design issues, in particular the need to identifya population of persons whose condition progressed during the finite periodof the trial, rather than therapeutic efficacy. This problem made separationof the placebo and active intervention arms problematic.

More promising in its potential effect on bone remodeling in OA are theresults of a recent preclinical investigation into the role of calcitonin [34].Further clinical trial results are eagerly anticipated.

Two of themore controversial areas of OAmanagement relate to the use ofglucosamine and the hyaluronans. Neither currently is approved foraDMOAD indication.Much of the symptomatic data on these agents suggestthat there is little difference between active agent and placebo in well-designedtrials [35–38]. Further controversy extends to whether they have any effect onstructure. Claims have been made that hyaluronic acids slow the rate of dis-ease progression, but the clinical results do not support this claim [30,39].Two published randomized longitudinal studies indicate that glucosaminesulfate slows the rate of progression of knee OA [40,41]. In these studies, how-ever, joint-space width was assessed using standing, anteroposterior kneeradiographs, and the findings have been criticized because a change in kneepain might affect the patient’s ability to extend the knee and thereby mightalter apparent joint-space width [42]. The results of the recently completedGlucosamine/Chondroitin Arthritis Intervention Trial, which included an18-month imaging outcome, have not been reported yet [37].

It has been reported that avocado/soybean unsaponifiables repress chon-drocyte catabolic activities and increase the accumulation of proteoglycanby OA chondrocytes in culture. Based on current clinical evidence, theirefficacy in modifying structure is questionable [43], but further trials aremerited, given the preliminary nature of this evidence.

What promising targets are being explored?

OA is a disease of the whole joint organ, and current drug developmenthas been directed toward a number of different tissue targets [44].

Synovitis frequently is present in OA and may predict other structuralchanges and correlate with pain and other clinical outcomes [45]. The syno-vium is densely innervated by small-diameter sensory nerve fibers [46]. Inter-leukin (IL)-1b and tumor necrosis factor (TNF)-a have the capacity toexcite and sensitize nociceptors and contribute in vivo to behavioral signs


of inflammatory hyperalgesia, for example through nerve growth factor(NGF) [44,47]. Moreover, cytokines enhance the release of prostaglandinE2, inducible nitric oxide synthase (iNOS), and histamine from chondro-cytes, meniscal cells, and mast cells, which in turn, indirectly, can increasethe sensitization of nociceptors [48].

Nitric oxide (NO)-dependent tissue injury has been implicated in OA[49]. The expression of iNOS (by endotoxin, cytokines, and/or other path-ophysiologic stresses) generates high, sustained concentrations of NO. Thesustained excess production of NO and resulting NO-derived metabolites(eg, peroxynitrate) elicit cellular cytotoxicity and joint-tissue damagethrough activation of MMPs, cytokines, and cyclo-oxygenase 2, producingalterations in normal physiologic function in the articular joint leading toOA changes. The widespread expression of iNOS in human OA tissues,including synovial, meniscal, osteophyte, and articular cartilage tissues[25,49–51], as well as data from a number of animal models of arthritis[52,53] and pain [54] suggest that iNOS inhibitors may have utility inthe treatment of OA.

Bradykinin is generated in inflamed synovium, as it is in all inflamed tis-sue, and is able to excite and sensitize sensory nerve fibers [55]. The clinicalrelevance of bradykinin has been demonstrated recently in a phase II studyin which intra-articular injection of a specific bradykinin-B2 receptor antag-onist reduced OA knee pain more potently than placebo injection [56].HOE140 is a specific and potent bradykinin-B2 receptor antagonist that isa decapeptide and is administered by intra-articular injection. In the firstplacebo-controlled proof-of-mechanism study in patients who had kneeOA, a single dose of HOE140 was given and provided greater pain reliefthan placebo injection [57].

Another target of interest is NGF. NGF exerts its action through twotypes of receptors: the high-affinity tyrosine kinase A receptor and thelow-affinity p75 receptor. Both NGF and its receptors are expressed in syno-vial, meniscal, and articular cartilage tissues, suggesting that they could beinvolved in joint physiopathology and OA [58,59]. RN624, tanezumab, isa humanized monoclonal antibody against NGF. In two recently completedrandomized, placebo-controlled, double-blind studies in patients who hadchronic OA pain, a single dose of tanezumab showed significant improve-ment in Western Ontario and McMaster University Osteoarthritis Indexscores compared with placebo [60].

Widespread use of TNF inhibitors and other biologic agents in the treat-ment of rheumatoid arthritis has led to unprecedented success in diseasemanagement. Intra-articular injection of specific IL-1 inhibitors or antago-nists has been shown to slow disease progression in animal models of OA. Incontrast, the first randomized placebo-controlled trial of an IL-1b antago-nist (a single intra-articular injection of 50 or 150 mg) had no analgesic effectduring 3 months of follow-up [61], although 150 mg of IL-1 receptor antag-onist had an early analgesic effect. Anti-TNFa therapy also has been tested


in isolated cases of digital and knee OA, with little success in clinical trials todate. Synovitis seems to have a role in symptoms but to be a response tocartilage degradation rather than a risk factor predisposing to it; therefore,it is likely that TNF inhibitors will impact only symptoms, not diseaseprogression.

Because of the importance of bone remodeling inOA, furtherwork recentlyhas been initiated investigating the potential structure-modifying role of vita-min D. Another promising line of inquiry is investigation into the role of thebone morphogenetic protein family of protein-signaling molecules [62].Another potential therapeutic target in OAmay be the strong vascularizationof areas of osteoarthritic bone remodeling [63]. There is evidence thatenhanced vascular pressure in subarticular bone regions (especially in thefemur or tibia), venous engorgement, and the chemical and mechanical stim-ulation of sensory nerve endings in the vascular wall or ischemia may contrib-ute to severe ischemia- and pressure-induced pain at rest or at night in patientswho have advanced hip or knee OA [64]. In this regard, preliminary investiga-tion of the role of iloprost, a synthetic analog of prostacyclin prostaglandin I2,seem promising but warrant further rigorous evaluation [65,66].

The rationale for leaving the discussion of agents that have activity inhyaline articular cartilage to last is to emphasize the importance of studyingother tissues. One of the major players during the breakdown of articular car-tilage is the proinflammatory cytokine IL-1b [44]. Chondrocytes and synovio-cytes produce and release IL-1b. Intracellularly, the pro-form of IL-1b isconverted by interleukin-converting enzyme (ICE) to the active form ofIL-1b. The importance of this enzyme has been elucidated by the study of pral-nacasan, an ICE inhibitor that reduced joint damage in twomurine models ofOA [67], and by gene transfer of a biologic IL-1 receptor antagonist [68]. IL-1bactivates proteases; these MMPs cleave collagen II (MMP-1, MMP-13) andconvert pro-MMPs into collagenases and gelatinases (MMP-3).

Other agents of particular interest are the cathepsin K and aggrecanaseinhibitors. Although characteristic of osteoclasts, the expression of cathepsinK also has been observed at other sites in skeleton. Several recent observa-tions have demonstrated that the expression of cathepsin K is increased inosteoarthritic cartilage and in inflamed synovial tissue [69]. Because cathepsinK is one of the few extracellular proteolytic enzymes capable of degradingnative fibrillar collagen, it may be important in the progressive destructionof articular cartilage both in OA and in inflammatory arthritides.

A major component of the cartilage extracellular matrix is aggrecan,a proteoglycan that imparts compressive resistance to the tissue. Aggrecan,a major component of the cartilage extracellular matrix, is cleaved at a spe-cific aggrecanase site in human osteoarthritic cartilage by several membersof the ADAMTS family of metalloproteases. ADAMTS5 is the primaryaggrecanase responsible for aggrecan degradation in a murine model ofOA [70], and inhibition of this protease now is undergoing clinicalinvestigation.


Obstacles to drug development

A number of well-known risk factors for structural progression of OA arelikely to be operational in the investigation and use of DMOADs [71].Greater attention to the pathogenesis of this complex disease is needed intherapeutic trials. A number of recent studies have highlighted the impor-tance of mechanical factors in the etiopathogenesis of this disease [72].Knee alignment and the stance-phase adduction moment [73] are key deter-minants of the disproportionate medial transmission of load [74]. Themechanics of the joint environment play a pivotal role, and ignoring theirimportance eliminates any chance of finding an effective product. Attemptsto treat a failing tissue in a grossly malaligned joint is equivalent to movingthe mountain. For effective trials of pharmacologic intervention as a singletherapy, it is preferable to select subjects who have less-advanced disease,before the development of marked aberrant mechanics. As Brandt andcolleagues [21] suggested, ‘‘If efforts to develop a DMOAD or biologicaltreatment for OA, which are almost always aimed at stimulating the osteo-arthritic cartilage with growth factors or inhibiting matrix-degradingenzymes, do not concomitantly correct the mechanical disorder that is theproximate cause of the arthropathy, these treatments are unlikely toproduce long-lasting benefit.’’

To identify change, current trials have needed more responsive outcomemeasures for both symptoms and structure. Clinical research efforts areongoing to develop and validate new pain and function questionnairesthat may be more sensitive in detecting improvement in patients’ symptoms[75,76]. As occurred in rheumatoid arthritis and osteoporosis, the advent ofone therapy that successfully modifies the disease will change the playingfield rapidly. Investigators and clinicians in the OA community are lookingforward to the time when this breakthrough in treatment will provide fertileground for further therapeutic development.

The development of many agents is being stopped because of inefficacy inanimal models, although the human model in which they ultimately may betried is markedly different. Alternate preclinical methods that more closelymimic the human condition are highly desirable to assess efficacy in humans.

Therapeutic development should be tailored toward the clinical presenta-tion. OA typically manifests with prominent symptoms in a limited numberof weight-bearing joints or in a few hand joints and lacks extra-articularmanifestations. As such, it is well suited to local therapy administered byintra-articular injection. Although injection into joints has side effects,many products given systemically may have systemic side-effect profilesthat would limit their chronic use in OA.

Similarly it is important to change the current paradigm of focusing onhyaline articular cartilage at the expense of other joint tissues that playa more pivotal role in disease symptoms and etiopathogenesis, especiallysynovium, bone, fat, meniscus, and ligaments. Investigators need to widen


their perspective, study these other important structures, and target themappropriately. Cartilage may reflect the underlying condition, but its con-tribution to symptoms and progression should not be considered in isola-tion. Obesity is the single most important risk factor for development ofsevere OA of the knee and has more predictive power than other poten-tially damaging factors, including heredity [77]. Important determinantsof the local mechanical environment of the knee joint are the integrityand function of the periarticular muscles, the meniscus, and the ligaments[78,79]. Despite the prominent role in disease etiopathogenesis played byobesity and these target tissues, they do not seem to have been targetedsufficiently through a biologic or pharmacologic approach for OA manage-ment. Their importance in disease suggests that they would be worthwhiletherapeutic targets.

Summary

Improving the understanding of the tissues in the joint other than hyalinecartilage (especially bone, fat, meniscus, and synovium) and the roles thesetissues play in OA pathophysiology probably will yield treatment break-throughs. Therapeutic development must consider that OA is a complex dis-ease with a wide variety of clinical presentations, and one single therapy isunlikely to be effective in treating this heterogeneous condition. In develop-ing these therapies, greater attention should be paid to the mechanics of thejoint environment. Promising therapies are being developed, but these con-siderations and obstacles to development must be heeded to if these effortsare to be effective.

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