Personalised Medicine and Disease Modification in Osteoarthritis: On our journey but still a way to go!
By Alan Reynolds and Nicholas Larkins
Introduction and Background
Osteoarthritis (OA) is the most prevalent joint disease, estimated to affect 250 million people worldwide with prevalence increasing due to aging populations and growing levels of obesity.1 The estimated global incident cases from the 2017 Global Burden of Diseases (GBD) study were almost 15 million with an age standardised incidence of 181.19 per 100,000, which was highest in the USA at 316.87 per 100,000.2
OA causes a substantial burden of disability, ranking third behind Alcohol Use and Unipolar Major Depression for Years Lost to Disability (YLDs) in the USA in 1996 totalling 434,000 YLDs, 5.9% of the total.3 Based on the 2010 GBD study, the combined incident case total of hip and knee OA was ranked as the 11th highest contributor to global disability and 38th highest in Disability Adjusted Life Years.4 Mobility disability due to OA is greater than any other disease and OA of the knee contributes 83% of the total burden attributed to OA.1 The quality of life (QoL) of patients with OA is substantially reduced, not only with respect to physical function but across other domains, including mental health.5-7
The socioeconomic impact is significant. In the USA, annual total costs for 2013 were estimated at $139.8 – $161.8 billion (direct $115.3 billion and indirect $11.6 – $13.0 billion).8 The social cost of OA could be as high as 2.5%9 of Gross Domestic Product although a recent systematic review reported values between 0.25 and 0.5%.10 A study from Sweden found that patients with knee OA have double the risk of sick leave with 2% of all days off work resulting from the disease and an increased risk of receiving a disability pension.11 In a survey of five European countries involving 3750 subjects, the mean SF-12 score* was 40.53 (perfect health =100] and 21.5% reported depression. Among the one third who were employed, 7% reported absenteeism and 24% presenteeism.12
*SF-12 is a self-reported short form outcome measure assessing the impact of health on an individual’s everyday life. It is often used as a quality-of-life measure.
The economic and QoL impact of OA led the Osteoarthritis Research Society International (OARSI) to submit a white paper to the US Food and Drug Administration (FDA) in 2016, “Osteoarthritis: A Serious Disease”,13 which resulted in the publication of draft guidance in 2018 that stated the “FDA recognizes that OA can be a serious disease with an unmet medical need for therapies that modify the underlying pathophysiology of the disease and potentially change its natural course to prevent long-term disability.”14
In this article we will discuss the challenges in demonstrating disease modification in OA, illustrate this with examples of recently published clinical trials, and then describe the current status of APPA, a novel, patented potential Disease Modifying Osteoarthritic Drug (DMOAD). APPA is an oral combination of two synthetically produced isomers, originally of plant origin: 4-hydroxy-3-methoxyacetophenone (apocynin) and 2-hydroxy-4-methoxyacetophenone (paeonol).
Pathophysiology of OA
OA is a disease of diarthrodial joints and had historically been considered to result from ‘wear and tear,’ leading to cartilage loss and reduction in the joint space resulting in pain and damage to the bone. Research over the last decades has established that OA involves the whole joint with not only loss of cartilage, but also changes in the subchondral bone, synovium, tendons, ligaments and muscles. It is now recognised that the disease process is more complex than originally assumed and, to a lesser or greater degree, involves chronic inflammation,15 mainly involving the innate immune system,16 triggered for example, by aging or obesity.17,18 Ageing of itself has important consequences with regard to OA, including low grade12 inflammation (inflamm-aging), mitochondrial dysfunction with oxidative stress, and cell senescence.19,20 It has now been established, however, that OA is a heterogenous disease with several different phenotypes and possible triggers that lead to a common final pathway resulting in jointdestruction.21-26 The roles of bone, cartilage, and synovium in OA with cross talk between them involves many different pathways and provides numerous potential treatment targets.27-29
Current Treatment of OA
Despite the importance of OA on patient QoL, the human cost of pain and disability caused, and economic costs, treatment options are limited. Unlike rheumatoid arthritis (RA), no interventions have been approved that alter the course of the disease – a pharmacopeia of DMOAD as the holy grail of OA treatment.
The primary reason subjects visit physicians with OA is because of pain. Recommendations for treatment pathways are available in a number of publications,30-33 most of which start with education, self-management and lifestyle interventions such as weight loss and increased exercise. Studies of pharmacological interventions most often involve the knee rather than other sites of OA and have been of limited duration focussing on pain as the primary outcome measure. It must be noted, however, that many subjects have multiple joint involvement and that the pain is chronic.
Oral analgesics such as acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs) are widely recommended but use of NSAIDs is limited due to toxicity34,35 and should be used at the lowest dose and the shortest possible time.33 Recent evidence however has questioned the efficacy of acetaminophen in OA.36-38 Topical NSAIDs are recommended as effective but without the safety concerns associated with the oral forms. In the event that pain relief is insufficient then opioids are an option with the associated concerns over long term use.
A number of injectable treatments are included (for example, corticosteroids) although there is evidence that repeated injections of corticosteroids may be associated with additional joint damage.39 These restricted treatment options and their limited effectiveness result in inadequate pain relief with associated impact on function.40 Intractable pain, loss of function and joint damage are criteria for surgical joint replacement which is frequently highly successful.34
Notwithstanding these interventions, there remains a high unmet need for effective analgesics for patients with osteoarthritis and treatments that slow, halt, or even reverse the slowly progressing joint damage.
Challenges for DMOAD clinical trials
The hope that drugs in development would achieve DMOAD status was initially discussed over 10 years ago,41,42however we seem still a long way from achieving that goal. Many challenges exist in the design and conduct of OA clinical trials43 particularly those attempting to identify DMOAD status.
Following submission of the OARSI white paper to the FDA in 2016,13 the Agency published draft industry guidance on structural endpoints for OA.14 The document laid out the considerations for approval of a drug as a DMOAD mainly for scenarios where an intervention has beneficial effects on a surrogate end point such as a soluble biomarker or structure that in the longer term is associated with clinical benefits such as reduction in pain, improvement in function, or delay or avoidance of joint replacement.
FDA concluded, however, “At this time, the ability of treatment effects on common measures of structural progression to reliably predict treatment effects on direct measures of how patients function and feel, has not been established.” Many challenges remain in design and implementation of such trials, not least being the different endotypes and phenotypes that have been identified, validation of the imaging endpoints, qualification of soluble biomarkers, and high pain placebo response rates.43 Several publications have discussed possible trial options, but much work remains to be done to optimise designs.44,45
Surrogate Endpoints and Biomarkers
Most of the current potential DMOADs do not have direct effects on clinical outcomes (pain, function, joint replacement). As outlined above, in order to receive marketing approval, studies will need to establish the interventions have beneficial effects on surrogate endpoints (e.g., imaging) or biomarkers which have been shown to predict clinical outcomes in the longer term.
The imaging standard in OA clinical trials has been radiographically measured minimum joint space width (mJSW), which equates to tibiofemoral cartilage loss. This has a number of drawbacks, including the contribution of other structures to changes in JSW as well as issues with alignment, positioning and sensitivity to change in a disease that progresses slowly in the majority of patients. In a large 1683 patient study treated with sodium ranelate, improvements were seen in both Joint Space Width (JSW) and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores,46 but concordance was not evaluated at the individual patient level. In 2015 OARSI published recommendations for use of radiography and Magnetic Resonance Imaging (MRI) in clinical trials to set standards and improve quality.47 Recent research has highlighted a range of different MRI approaches that are claimed to have greater sensitivity which are able to assess changes in overall joint structure48,49 and correlate with risk of joint replacement,50 although more data are needed to gain acceptance by regulatory authorities as a suitable surrogate endpoint.
In OA, biomarkers have a number of potential roles which include stratification of patient subgroups, measurement of disease activity and response to treatment. This would also involve identification of patients who will likely show progression of disease assessed by imaging, which provides potential surrogate endpoints and has the potential to identify the most appropriate treatment for an individual (i.e., personalised medicine, which Is still an aspirational goal).
The landscape of biomarkers has been reviewed recently51-53 and a number of important observations can be made. Firstly, none of the biomarkers to date have been approved for use by a regulator. However, serum cartilage-oligomeric matrix protein (sCOMP), urine Carboxy-terminal telopeptide fragments of type II collagen (uCTX-II), and MMP-generated fragment of C-reactive protein (CRPM) levels show promise as predictors of disease progression.54-56
Such promise is dampened by a study utilizing the Osteoarthritis Initiative Biomarkers cohort that reported that systemic biomarkers of bone turnover had only had weak associations with bone features.57 A proposed model from a recent analysis of two phase 3 clinical trials with salmon calcitonin combines baseline age, sex, BMI, u-CTX-II and X-ray KL-grade to predict total joint replacement (TJR) during a two-year period with an AUC of 0.75 (95% CI: 0.72-0.77).58 These approaches could improve patient selection for clinical trials of potential DMOADs.
Current DMOAD candidates
The increasing understanding of the complex pathways involved in OA has resulted in novel potential therapeutic targets being proposed with development of interventions designed to modify disease progression.59-63 These may be broadly classified into agents that:
- target cartilage turnover;
- target subchondral bone metabolism; or
- inhibit the inflammatory pathways that drive cartilage and bone 59,61
Table 1 summarises drugs that have recently completed or are currently in Phase 2 clinical trials as potential DMOADs. We will discuss four examples of agents that have reported results from these early clinical trials that illustrate the challenges faced with OA clinical trials and in demonstrating disease modification.
Lorecivivint (SM04690), a small molecule, is a Wnt pathway modulator acting via CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) leading to reduced STAT3 and NF-κB signalling, resulting in reduced in matrix metalloproteinase activity and reduced inflammatory cytokine production.64,65
A small Phase 1 study in subjects with knee OA showed potential analgesic and DMOAD effects.66 In the Phase 2A study however, there was no significant difference in improvement in WOMAC pain score when compared with placebo at week 13, and no effects on mJSW at 52 weeks were seen.67 Results from the biomarkers ß-CTX, PINP and COMP were inconclusive. Post hoc analyses however, demonstrated significant improvements in pain scores in all dose groups in subjects with unilateral OA and those with unilateral involvement and absence of widespread pain. Unilateral knee OA subjects treated with the 0.07 mg dose had significantly increased mJSW compared to placebo. Importantly there was concordance between WOMAC pain and mJSW measurements.
A Phase 2B 24-week study enrolled patients with unilateral knee OA. The primary endpoint, change in pain Numerical Rating Scale (NRS), was achieved by the 0.07 and 0.23 mg dose groups but no dose group demonstrated benefit on mJSW.68 A post hoc analysis showed that subjects with a baseline mJSW of 2-4mm had increased sensitivity to radiographic change.69
The variable results seen between the studies clearly illustrate the challenges faced in studies evaluating potential DMOADs. Post hoc analyses have been used, however, to inform the design of the Phase 3 studies, which started enrolling subjects in June 2019.70 The completed Phase 2 studies discussed above did not include biomarkers in the information posted on ClinTrials.gov. However, a recently completed (but not reported) Phase 2 study (NCT03727022) with a primary endpoint of change in bone mineral density does include the serum bone turnover biomarkers and cartilage metabolism.71
Sprifermin, a recombinant form of truncated human fibroblast growth factor 18, is administered by intra-articular injection that induces expansion of hyaline cartilage producing chondrocytes72 and remodelling of cartilage in human OA explants.73
Two Phase 1 studies have been completed: the first study being a single ascending dose study (SADS) followed by the second study, a multiple ascending dose (MAD) safety study that showed no evidence of any safety issues.74 A Phase 1B Proof of Concept study compared 3 doses of sprifermin with placebo in a SAD/MAD design. The MAD portion evaluated 3 injections one week apart with a second round of 3 injections 12 weeks after the first injection. The study did not achieve the primary endpoint, quantitative magnetic resonance imaging (qMRI) change in central medial femorotibial compartment cartilage thickness. Evidence of benefit was reported though on prespecified secondary qMRI endpoints. Subjects receiving sprifermin reported less improvement in WOMAC pain than those given placebo, which was significant for the highest dose group, 100µg.75
The Phase 2 study compared two doses of sprifermin, administered every 6 or 12 months, with placebo in patients with symptomatic OA. Injections were given as weekly injections over a 3-week period. The primary end point was change in qMRI total femorotibial joint cartilage thickness after 2 years compared with placebo which was achieved by both 100μg doses but not the 30μg doses. Dose dependant increases in cartilage thickness and volume were also reported. None of the 4 sprifermin doses achieved significant differences from placebo for WOMAC total scores or subscale scores although all groups showed improvements from baseline.76 At the Year 3 follow- up, 18 months after the last injection however, the WOMAC pain scores versus placebo were significant.77
Synovial fluid biomarkers of cartilage metabolism, PRO-C2 (type II collagen formation), huARGS (aggrecan degradation), and FBN-C (fibronectin degradation), were evaluated in a subset of subjects from the Phase 2 study and showed a phasic pattern. There was an overall increase in ARGS over time in the sprifermin group but after each cycle of injections levels decreased, whereas ARGS simply decreased over time in the placebo group. There was an initial decrease in collagen formation measured by PRO-C2 after sprifermin injections, followed by increases, so that at the end of follow-up, levels had increased from baseline, whereas no change was seen over time in the placebo group. Similar results were seen with fibronectin.78 These temporal changes seen with the biomarkers suggest that with respect to sprifermin, these biomarkers may not be ideal for assessing response to treatment or acting as surrogates for clinical response.
Cathepsin K is a protease found in osteoclasts and is involved in bone resorption through cleavage of type I collagen. It is also expressed in synovium and chondrocytes and causes degradation of type II collagen in cartilage.79 MV-711 is an oral, highly selective inhibitor of cathepsin K and has been shown to reduce bone and cartilage degradation dose-dependently in monkeys and humans80 and to reduce bone and cartilage loss in animal models of OA.81
The Phase 2A study compared 200 mg/day and 100 mg/day with placebo.82 The primary endpoint was change from baseline in NRS pain score for the target knee over the 26-week study period. In both MIV-711 treatment and placebo groups, pain scores reduced from baseline but there were no differences between the groups.
The key secondary imaging outcomes were assessed by MRI. Both doses of MIV-711 significantly reduced medial femoral bone area progression and medial femoral cartilage thinning versus placebo. Levels of biomarkers of bone resorption (CTX-I) and cartilage degradation (CTX-II) were reduced by both doses compared with placebo. Although MIV-711 clearly had effects on bone and cartilage seen by imaging and biomarker analysis over 26 weeks there was no symptomatic benefit. On the other hand, data from the Osteoarthritis Initiative found that changes in bone structure over 2 years do not translate into pain worsening until 4 years,83 so the study may have been too short to detect symptomatic benefit.
APPA is being developed by AKL Research and Development Ltd for treatment of osteoarthritis in association with NBCD A/S (previously Nordic Bioscience Clinical Development). Recruitment of subjects into the Phase 2 clinical trial (NCT04657926) began in September 2020.
In vitro studies with activated human neutrophils have found that APPA does not interfere with neutrophil host defence against infections but does inhibit neutrophil degranulation and production of neutrophil extracellular traps.84 APPA also down-regulated TNFα-stimulated NF-κB gene expression, but up-regulated expression of Nrf2, transcription factors involved in control of inflammation and response to redox stress, both of which (Nrf2 and NF- κB) interact with each other.85 In addition, both have been identified as potential targets in OA.86,87
Research utilising ex vivo tissue explants conducted by Nordic Biosciences A/S** found that APPA reduces inflammation-derived tissue turnover in human cartilage explants and inhibits RANKL-mediated osteoclastogenesis and bone resorption by human osteoclasts. Studies** using human chondrocytes undertaken by Instituto de Investigación Biomedica da Coruña reported that APPA significantly reduced the gene expression induced by IL-1β of IL-8, TNF-α, MMP-13 and MMP-3. In addition, in experiments with human cartilage explants stimulated with IL-1β, APPA significantly increased levels of proteoglycans in the intermedial layer. The results from these sets of experiments suggest that APPA affects a number of processes in joint tissues that contribute to damage in patients with OA. This conclusion is supported by results from the rat meniscal tear model of OA. APPA treatment reduced modification of the OARSI Total Joint Score88 by 21% compared to animals that received vehicle alone.89
**Submitted to the 2021 OARSI meeting.
In a cross-over study in dogs with naturally occurring OA that compared APPA with underwater treadmill therapy and massage, APPA reduced pain assessed by force plate measurements and normalised gait symmetry.90 A second 28-day dog study compared APPA with meloxicam plus famotidine and placebo. Both active treatment groups had significant improvements from baseline for orthopaedic score. The APPA group had significantly better scores for lameness at the walk and lameness at trot compared with the placebo group.91
The effects of APPA in a case series of human subjects with OA was recently reported in abstract form. Twenty-three subjects with a diagnosis of OA of whom 7 were scheduled for surgery have been treated with APPA. Treatment was deemed effective in 19 and, in the 16 subjects where information was available, duration of treatment ranged from 9 to 120 (median 24) months and was well tolerated.92
A Phase 2 study comparing APPA to placebo in 150 patients with knee OA has recently started. In view of the data from the animal studies and the human case series, the primary endpoint is reduction in pain over 28 days. Evidence to support potential DMOAD effects, as demonstrated in the rat meniscal tear model of OA, will be determined with biomarkers. Information from the ex vivo experiments has been evaluated to select the most appropriate biomarkers that reflect the pathways impacted by APPA, cartilage degradation by aggrecanase and MMPs, and bone turnover.
This approach differs from the examples discussed above as there is evidence that the effect on symptoms occurs early in treatment and is not dependent on structural effects. In this respect APPA is more like biological treatments for RA than other potential DMOADs currently in clinical trials.
Discussion and Conclusions
Addressing the substantial unmet needs in the treatment of OA, both for reduction of pain and for reducing the progression of disease starts with an understanding of the nature of OA as a heterogenous disease with a number of phenotypes with different pathways to joint damage. Personalised medicine has long been an aspirational goal of OA treatment93-94 and the scientific and clinical community and pharmaceutical companies have devoted much time, effort and money to achieve that target, but many obstacles remain.
OA is usually a slowly progressing disease so demonstrating reduction in the rate of damage is challenging. These difficulties have been reviewed recently43 and proposals for study designs in the light of the FDA draft guidance have been published.44,45 A premise of current investigational DMOADs is that effects on structural changes will lead to improvements in clinical endpoints such as pain and function. This assumption has been challenged recently95 as analysis of data from the Osteoarthritis Initiative led to the conclusion that cartilage loss resulted in limited worsening of pain.
The difficulties in assessing and demonstrating disease modification has been illustrated by the 3 examples with published results as discussed above. We look forward to resolving these difficulties eventually through additional research studies enriched with OA subjects whose disease is likely to progress and to explore the correlations between biomarkers, surrogate endpoints and clinical outcomes.
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Alan is Chief Scientific Officer and Director of AKL Research and Development Ltd. He graduated from Brunel University with an honours degree in Applied Biology before working in the antimicrobial discovery section at Glaxo, undertaking microbiology research at The Royal Free Hospital in London and acting as a Teaching Fellow at the University of London School of Pharmacy. He then rejoined the pharmaceutical industry with Ayerst (later merged with Wyeth and Lederle) in the Medical Affairs Department. Over the years he worked in a number of therapeutic areas including female health, gastroenterology and diabetes. As a member of the global strategy teams he was involved in the development of the block buster drugs Effexor and Enbrel. He was project lead for the successful submissions to the National Institute for Health and Clinical Excellence (NICE) for Enbrel and was appointed Clinical Science Director for Europe in 2007. He received several company awards including two President’s Awards for Excellence. Following the takeover of Wyeth by Pfizer in 2009 he chose to leave the corporation and worked as a consultant for a number of companies. He joined AKL in 2018. He is a member of the Treatment Subcommittee of the UK Charity Versus Arthritis and the author of 1 book chapter, 29 papers, 5 letters and 47 abstracts.
Nicholas is the Chief Research Officer and a Director of AKL Research and Development Ltd. A graduate in veterinary science from Sydney University and a Member of the Royal College of Veterinary Surgeons, he has been an invited Lecturer to Conferences in Australia, United Kingdom, Dubai, Spain, Italy, Belgium, The Netherlands, USA and Switzerland. Since 1998 he has been involved in ongoing post-graduate study, research with published papers in pharmacognosy, nutritional medicine and reactive oxygen species (biology and pathology). He has extensive research interests in pharmacognosy specifically focused on immunomodulatory phyto-pharmaceuticals and the roles they play in inflammation and the resolution of inflammation. He was a veterinary advisor and clinical consultant to the U.K., Spanish, New Zealand and Swedish Equestrian Teams for the Seoul Olympics, 1988: to U.K., New Zealand, United Kingdom and Australian Equestrian Teams for the Barcelona Olympics 1992 and to New Zealand Equestrian Team for the Sydney Olympics 2000. Ongoing research projects and clinical trials involve collaborations with the University of Aberdeen (UK), The Animal Health Trust (Newmarket- UK), The University of Utrecht (Holland), The University of Vienna (Austria), University of East Anglia (UK), Knight Scientific Laboratories (UK), Warwickshire Agricultural College (UK), Royal Agricultural University (UK), Bolder Biopath (USA), The University of Surrey (UK), The University of Liverpool. (UK), INIBIC-Instituto de Investigación Biomedica da Coruña (Spain) and Nordic Bioscience Clinical Development (NBCD) (Denmark).