Potential Disease-modifying Osteoarthritis Drug Research Articles

Disease-modifying osteoarthritis drugs (DMOADs): new trends in osteoarthritis therapy

The review examines pharmacological agents that can have potential disease-modifying osteoarthritis drugs (DMOADs) status. DMOADs prevent the progression and further structural joint damage (structure-modifying effect), leading to a decrease in symptoms severity (symptom-modifying effect), such as pain, and improvement of joint function. Approaches to potential DMOADs selection are discussed: (1) the preferred target (bone, cartilage, synovia); (2) action drug mechanism/anti-cytokine therapy (matrix metalloproteinase inhibitors, inhibitors of pro-inflammatory interleukins, etc.). The main delivery systems of drugs claiming to be of DMOADs status and possible contribution of immunological mechanisms to osteoarthritis pathogenesis are considered. Methods evaluating the effectiveness of DMOADs therapy are of great interest (cytology, microscopy, radiological research methods, blood and synovia biochemical markers). Based on research results analysis, the following substances can be considered as potential DMOADs: chondroitin sulfate, glucosamine sulfate, undenatured type II collagen, vitamin D. Each of them has symptom-modifying and structural-modifying effects.

Creation of a Knee Joint-on-a-Chip for Modeling Joint Diseases and Testing Drugs

The high prevalence of debilitating joint diseases like osteoarthritis (OA) poses a high socioeconomic burden. Currently, the available drugs that target joint disorders are mostly palliative. The unmet need for effective disease-modifying OA drugs (DMOADs) has been primarily caused by the absence of appropriate models for studying the disease mechanisms and testing potential DMOADs. Herein, we describe the establishment of a miniature synovial joint-mimicking microphysiological system (miniJoint) comprising adipose, fibrous, and osteochondral tissue components derived from human mesenchymal stem cells (MSCs). To obtain the three-dimensional (3D) microtissues, MSCs were encapsulated in photocrosslinkable methacrylated gelatin before or following differentiation. The cell-laden tissue constructs were then integrated into a 3D-printed bioreactor, forming the miniJoint. Separate flows of osteogenic, fibrogenic, and adipogenic media were introduced to maintain the respective tissue phenotypes. A commonly shared stream was perfused through the cartilage, synovial, and adipose tissues to enable tissue crosstalk. This flow pattern allows the induction of perturbations in one or more of the tissue components for mechanistic studies. Furthermore, potential DMOADs can be tested via either "systemic administration" through all the medium streams or "intraarticular administration" by adding the drugs to only the shared "synovial fluid"-simulating flow. Thus, the miniJoint can serve as a versatile in vitro platform for efficiently studying disease mechanisms and testing drugs in personalized medicine.

Sprifermin for Treatment of Osteoarthritis: Recombinant Fibroblast Growth Factor 18 as a Possible Disease-Modifying Knee Osteoarthritis Drug

Osteoarthritis (OA) is a major cause of pain and disability in adults, affecting approximately 150 million people worldwide. It is most prevalent in knees and hips. Major risk factors are age, female sex, prior joint injury, and obesity. OA causes significant personal and steeply rising socio-economical costs in ageing populations. OA is characterized by progressive cartilage damage and inflammation. In later stages, it affects the subchondral bone, bone marrow, ligaments, tendons, and nerves und eventually leads to joint failure. Symptoms include pain, joint swelling, and stiffness. Therapies are symptomatic and focus on pain relief and measures to improve mobility, or, ultimately, joint replacement. So far, no drugs that could prevent or slow down disease progression are available. Based on promising in vitro and preclinical studies, recombinant fibroblast growth factor (FGF) 18 (sprifermin; Merck Serono) has come into focus as a potential disease-modifying OA drug (DMOAD). Three randomized controlled trials (RCTs) investigating the safety and efficacy of intraarticularly (i.a.) injected sprifermin application in patients with knee OA have been completed so far. Data from these trials, post hocanalyses and follow-ups provide have evidenced that i.a. sprifermin induced a significant and sustained increase in cartilage thickness and volume without specific adverse effects, but in terms of clinical symptoms or physical joint function sprifermin did not cause significant improvements compared to placebo treatment in whole study populations. However, significant pain reduction was observed in a “subgroup at risk” of patients with more severe disease states, indicating that under certain disease conditions the structural benefit improvements could translate into clinical benefit. This calls for larger RCTs allowing e.g., for disease state or risk factor-specific stratification of patients and longer follow-ups to substantiate the efficacy of sprifermin as a possible DMOAD. This review gives an overview on the prevalence, etiology and socio-economic burden of OA, its pathogenesis as well as the current treatment options of the disease. It summarizes the role of FGF-18 in chondrocyte and cartilage (patho)physiology and addresses the question of evidence for the efficacy and safety of i.a. sprifermin injection in patients with knee OA based on trial outcomes and literature data.

PREVALCENCE OF MR‐DECTED CARTILAGE DAMAGE IN KNEES WITH KELLGREN-LAWRENCE 2 & 3 OSTEOARTHRITIS AND IMPLICATIONS FOR CLINICAL TRIALS

Many potential disease-modifying osteoarthritis drugs (DMOADs) have been investigated, but to date no DMOADs that slow or stop disease progression have been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A potential reason for the lack of demonstrated efficacy may be reliance on radiographs for defining structural inclusion and exclusion criteria for clinical trials, such as use of joint space width and Kellgren-Lawrence (KL) grade as surrogates for cartilage damage. To estimate the distribution of cartilage damage seen on knee MRI in a sample of knees with radiographic KL 2 and 3 OA that would potentially qualify for a DMOAD trial. We selected knees from the Osteoarthritis Initiative (OAI) that met common structural inclusion criteria for DMOAD trial enrollment at OAI baseline: knees with radiographs centrally graded as KL 2 or 3 and medial minimum joint space width (mJSW) ≥ 1.5mm. A musculoskeletal radiologist with 10 years of experience in semi-quantitative MRI assessment scored knee cartilage damage in the medial and lateral tibiofemoral and patellofemoral compartments using WORMS (Whole-Organ Magnetic Resonance Imaging Score). Coronal intermediate weighted (IW) TSE and sagittal fat-suppressed IW TSE sequences on 3T MRI were used. The WORMS cartilage scores, which are based on both the extent and depth of cartilage damage, were collapsed into 4 categories: no cartilage damage (WORMS 0 and 1), focal partial or full-thickness (PT/FT) cartilage damage (WORMS 2 and 2.5), diffuse partial thickness (PT) cartilage damage (WORMS 3 and 4), and diffuse full-thickness (FT) cartilage damage (WORMS 5 and 6). We estimated the prevalence of each category of cartilage damage in KL2 and KL3 knees; 95% confidence intervals (CI) accounted for clustering at the participant-level since some participants contributed two knees to the analysis. We identified 2,372 participants contributing 3,446 knees with radiographic OA (KL 2 and 3) and medial mJSW ≥ 1.5mm. There were 2,318 KL2 knees and 1,128 KL3 knees. We found no cartilage damage in any compartments in 9.8% (95%CI: 8.5, 11.1) of KL2 knees and 2.0% (95%CI: 1.1, 2.9) of KL3 knees. Cartilage damage was absent in the medial tibiofemoral compartment in 52.4% (95%CI: 50.1, 54.6) of KL2 knees, and 14.4% (95%CI: 12.2, 16.6) of KL3 knees, versus 61% (95%CI: 58.8, 63.2) of KL2 knees and 53.6% (95%CI: 50.4, 56.7) of KL3 knees in the lateral compartment. When medial and lateral compartments were combined, cartilage damage was absent in 34.8% (95%CI: 32.7, 36.9) of the KL2 knees, and 4.3% (95%CI: 3.0, 5.5) of the KL3 knees. Diffuse FT cartilage lesions in the medial compartment were found in 6.1% (95%CI: 5.0, 7.1) of KL2 knees and 42.5% (95%CI: 39.4, 45.6) of KL3 knees. MRI screening prior to clinical trial enrollment may identify a substantial percentage of knees with normal cartilage, as well as knees with diffuse FT cartilage lesions that may not be responsive to DMOADs, depending on the mode of action of a given pharmacological compound. AG has received consultancies fees from Pfizer, Novartis, AstraZeneca, Merck Serono, Regeneron and TissueGene and is shareholder of Boston Imaging Core Lab (BICL), LLC a company providing image assessment services. FWR is shareholder of BICL, LLC and has received consultancies fees from Calibr–California Institute of Biomedical Research and Grünenthal, GmbH. DH receives publication royalties from Wolters-Kluwer. CKK has received consultancy fees from Thuasne, Regeneron, Novartis, Kolon Tissue Gene, Taiwan Liposome, Amzell AZ, LG Chem, Express Scripts, and has received grants from Lilly, Pfizer GSK, Cumberland CORRESPONDENCE ADDRESS: mjarraya@mgh.harvard.edu .

Development of a selective matrix metalloproteinase 13 (MMP-13) inhibitor for the treatment of Osteoarthritis.

Osteoarthritis (OA) is a chronic disorder that causes damage to the cartilage and surrounding tissues and is characterized by pain, stiffness, and loss of function. Current treatments for OA primarily involve providing only relief of symptoms but does not affect the overall trajectory of the disease. A major goal for treating OA has been to slow down or reverse disease progression. Matrix metalloproteinase-13 (MMP-13) is expressed by chondrocytes and synovial cells in human OA and is thought to play a critical role in cartilage destruction. Herein we report a new, allosteric MMP-13 inhibitor, AQU-019, that has been optimized for potency, metabolic stability, and oral bioavailability through a combination of structure activity relationship (SAR) and deuterium substitution as a potential disease modifying OA drug (DMOAD). The inhibitor was demonstrated to be chondroprotective when injected intraarticular (IA) in the monoiodoacetic acid (MIA) rat model of OA.

ε-Poly-l-lysine as an efficient cartilage penetrating and residing drug carrier with high intraarticular injection safety for treating osteoarthritis

A major reason that hinders the clinical application of disease-modifying osteoarthritis drugs (DMOADs) is the unmet challenges in their effective delivery to cartilage. Cationic macromolecules represent promising carriers to enhance the drug delivery to cartilage through their electrostatic interaction with the negatively charged cartilage matrix. However, current candidate cationic macromolecular carriers (CMCs) must solve the intractable challenges in scalable production and biosafety before they can be used clinically. ε-poly-l-lysine (ε-PLL) is a unique poly (amino acid) that has favorable features to conquer the above issues. In this study, we evaluated the potential of ε-PLL as a cost effectiveness, biosafety, and effective CMC for drug delivery to cartilage. Cartilage explant from pig knee was used as a model for the in vitro analysis of ε-PLL’s interaction with, penetration into, and resident in cartilage tissue. The results showed that ε-PLL had a strong distribution tendency in cartilage with partition coefficient K ∼ 4.3 and weak cartilage matrix binding ability (KD ∼ 310 μM) with abundant intra-cartilage binding sites (N ∼ 9900 μM). Furthermore, ε-PLL could also penetrate full thickness cartilage and showed a long-time retention in cartilage explants and mouse joint cavity. The results of in vitro and in vivo toxicity tests showed nearly no negative impact of ε-PLL (100 μg/mL) on chondrocytes or local tissue. Using kartogenin (KGN, a potential DMOAD) as a model drug, the effectiveness of ε-PLL to improve the drug bioavailability in a mouse OA model was proved. Together, these results suggest that ε-PLL can be used as an effective and safe CMC for effective DMOAD delivery to cartilage.

Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study

ObjectiveThe FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here,...

New Trends in Pharmacological Treatments for Osteoarthritis.

Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.

Intra-articular drug depots for controlled release of heavy chain only antibodies blocking joint inflammation

Purpose: In many inflammation-driven diseases, blocking IL-1 signaling can be a potential strategy to help restore normal homeostasis. The modified recombinant version of IL-1RA, known by the name Anakinra, which competes with IL-1β is seen as a potential disease modifying osteoarthritis drug (DMOAD). However, as with many therapeutic proteins it shows a short half-life and loss of bioactivity. Currently, this problem is addressed by frequent injections of high doses of therapeutic proteins that is associated with unwanted side effects and patient morbidity.

Intra-articular sprifermin therapy reduces total knee replacements: accumulated evidence from translational and clinical data

Purpose: Osteoarthritis (OA) is a degenerative disease with high prevalence, creating an unmet medical need for drugs to protect and regenerate cartilage. Sprifermin, a truncated form of fibroblast growth factor 18 (rhFGF18), is being investigated as a potential disease-modifying OA drug (DMOAD). Sprifermin has been shown to increase cartilage volume in the knees of OA patients. Studies published about the mode of action clearly demonstrate anabolic effects. Accumulated analysis of data available from preclinical experiments and clinical data was performed to investigate the effects of sprifermin on late stage OA tissues as well as the rate of total knee replacements (TKR) in late stage OA patients.

The “placebo effect” in osteoarthritis clinical trials: challenging the narrative

Purpose: The Results of randomized controlled trials of potential disease-modifying osteoarthritis drugs (DMOADs) often show a precipitous decline in the estimated mean pain score for the active treatment arm and the placebo arm during follow-up. The decrease in the mean pain score in the placebo arm is often attributed to the placebo effect, which has been defined as “a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment”.

Intra-Articular Injection of (-)-Epigallocatechin 3-Gallate (EGCG) Ameliorates Cartilage Degeneration in Guinea Pigs with Spontaneous Osteoarthritis.

Osteoarthritis (OA) is the most prevalent joint disease that causes an enormous burden of disease worldwide. (−)-Epigallocatechin 3-gallate (EGCG) has been reported to reduce post-traumatic OA progression through its anti-inflammatory property. Aging is the most crucial risk factor of OA, and the majority of OA incidences are related to age and not trauma. In this study, we assess whether EGCG can ameliorate cartilage degradation in primary OA. In an in-vitro study, real-time PCR was performed to assess the expression of genes associated with human articular chondrocyte homeostasis. A spontaneously occurring OA model in guinea pigs was used to investigate the effect of EGCG in vivo. OA severity was evaluated using Safranin O staining and Osteoarthritis Research Society International (OARSI) scores, as well as by immunohistochemical (IHC) analysis to determine the protein level of type II collagen (Col II), matrix metalloproteinase 13 (MMP-13), and p16 ink4a in articular cartilage. In the in-vitro study, EGCG increased the gene expression of aggrecan and Col II and decreased the expression of interleukin-1, cyclooxygenase 2, MMP-13, alkaline phosphatase, Col X, and p16 Ink4a; EGCG treatment also attenuated the degraded cartilage with a lower OARSI score. Meanwhile, IHC results showed that EGCG exerted an anti-OA effect by reducing ECM degradation, cartilage inflammation, and cell senescence with a less-immunostained Col II, MMP-13, and p16 Ink4a. In conclusion, these findings suggest that EGCG may be a potential disease-modifying OA drug for the treatment of primary OA.

Lorecivivint, an intra-articular potential disease-modifying osteoarthritis drug

ABSTRACT Introduction: Osteoarthritis (OA) is the most common form of arthritis. Knee OA is associated with joint pain, activity limitation, physical disability, reduced health-related quality of life, and increased mortality. To date, all pharmacologic treatments for OA are directed toward pain management. Lorecivivint (LOR) is an investigational agent that has potential as a disease-modifying osteoarthritis drug (DMOAD). It modulates the Wnt signaling pathway by inhibiting CDC-like kinase 2 and dual-specificity tyrosine phosphorylation-regulated kinase 1 A which are molecular regulators in Wnt signaling, chondrogenesis, and inflammation. Areas covered: This paper discusses the current pharmacologic guidelines for the treatment of knee OA and illuminates the potential of a new agent, Lorecivivint, as a disease-modifying osteoarthritis drug (DMOAD). Efficacy and safety and the challenges for this novel agent come under the spotlight. Expert opinion: LOR may be a potential DMOAD for the treatment of patients with knee OA. While the Phase 2A trial did not meet its primary endpoint, preplanned analyses did identify a target population for further evaluation of its potential as a DMOAD. Phase 3 trials are ongoing, but this intra-articular drug is currently considered safe and well tolerated, with no significant reported systemic side effects.

Automated MRI assessment confirms cartilage thickness modification in patients with knee osteoarthritis: post-hoc analysis from a phase II sprifermin study

Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug. Previously, 2-year results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial compartments (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative magnetic resonance imaging (qMRI) using manual segmentation. To determine whether qMRI findings from FORWARD could be reproduced by an independent method of automated segmentation using an identical dataset and similar anatomical regions in a post-hoc analysis. Cartilage thickness was assessed at baseline and 6, 12, 18 and 24 months, using automated cartilage segmentation with active appearance models, a supervised machine learning method. Images were blinded for treatment and timepoint. Treatment effect was assessed by observed and adjusted changes using a linear mixed model for repeated measures. Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 years with sprifermin vs placebo for TFTJ (overall treatment effect and dose response, both P<0.001), MFTC (P=0.004 and P=0.044), and LFTC (both P<0.001) regions. For highest dose, in the central medial tibial (P=0.008), central lateral tibial (P<0.001) and central lateral femoral (P<0.001) regions. Cartilage thickness assessed by automated segmentation provided a consistent dose response in structural modification compared with manual segmentation. This is the first time that two independent quantification methods of image analysis have reached the same conclusions in an interventional trial, strengthening the conclusions that sprifermin modifies structural progression in knee osteoarthritis.

Long-term efficacy and safety of intra-articular sprifermin in patients with knee osteoarthritis: results from the 5-year forward study

Purpose: The 5-year Phase II FORWARD study assessed the efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin (recombinant human fibroblast growth factor 18) in patients with symptomatic, radiographic knee osteoarthritis (OA). The primary endpoint assessed at Year 2 showed dose-dependent modification of total femorotibial joint (TFTJ) cartilage thickness with sprifermin vs placebo (PBO) by quantitative magnetic resonance imaging (qMRI), and this was found to be sustained at Year 3 follow-up in a subsequent exploratory analysis.

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study.

ObjectiveAn ideal disease modifying osteoarthritis drug (DMOAD) has chondroprotective, anti-inflammatory, and analgesic effects. This study describes the production and characterization of a canine IL4-10 fusion protein (IL4-10 FP) and evaluates its in vivo DMOAD activity in a canine model of osteoarthritis (OA).DesignThe canine Groove model was used as an in vivo model of degenerative knee OA. Six weeks after OA induction dogs were intra-articularly injected weekly, for ten weeks, with either IL4-10 FP or phosphate buffered saline (PBS). In addition to the use of human IL4-10 FP, canine IL4-10 FP was developed and characterized in vitro, and tested in vivo. Force plate analysis (FPA) was performed to analyze joint loading as a proxy measure for pain. After ten weeks dogs were euthanized and cartilage and synovial tissue samples were analyzed by histochemistry (OARSI scores) and biochemistry (cartilage proteoglycan turnover).ResultsRepetitive intra-articular injections with human IL4-10 FP led to antibody formation, that blocked its functional activity. Therefore, a canine IL4-10 FP was developed, which completely inhibited LPS-induced TNFα production by canine blood cells, and increased proteoglycan synthesis of canine cartilage in vitro (p = 0.043). In vivo, canine IL4-10 FP restored the, by OA impaired, joint loading (p = 0.002) and increased cartilage proteoglycan content (p = 0.029).ConclusionsThis first study on the potential DMOAD activity upon prolonged repeated treatment with IL4-10 FP demonstrates that a species-specific variant has anti-inflammatory and chondroprotective effects in vitro and chondroprotective and analgesic effects in vivo. These data warrant further research on the DMOAD potential of the IL4-10 FP.

A cross-sectional survey of orthopaedicians to understand the prescribing pattern of disease modifying osteoarthritis drugs in osteoarthritis

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Numerous dietary supplements with disease-modifying action are available in Indian market. However, doctor’s preferences for these disease modifying osteoarthritis drugs (DMOADs) to prevent progression of OA are not known. The objective of this study was to quantify doctor preferences for potential DMOADs.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; The survey instrument (online survey questionnaire at survey monkey) was developed by researchers upon review of existing literature and detailed discussion with practicing clinicians. Face and content validity and reliability (test-retest method) was assessed through a focused panel of clinicians to determine if content was adequate to obtain the necessary data. This was a cross-sectional digital survey of 207 orthopaedicians during Indian Orthopaedic Association Conference-2018 organized at Coimbatore.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; NSAIDs + DMOAD combinations were the most preferred treatment option for newly diagnosed OA patients. 44% orthopaedicians prefer to start the treatment with combination of NSAID and DMOAD as compared to 10% with paracetamol monotherapy. Glucosamine/chondroitin combinations are the most commonly preferred DMOAD by the orthopaedicians; followed by undenatured type II collagen. 66% of the doctors surveyed opined that the efficacy of undenatured type-II collagen is better as compared to other DMOADs.&lt;/p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt;The findings from the survey suggest that majority of orthopaedicians prefer to prescribe NSAID with DMOAD combinations for newly diagnosed osteoarthritis patients.&lt;p&gt; &lt;/p&gt;

Efficacy and safety from a phase 2B trial of SM04690, a novel, intra-articular, WNT pathway inhibitor for the treatment of osteoarthritis of the knee

Purpose: A phase 2a study of SM04690, a small molecule, intra-articular (IA) Wnt pathway inhibitor, demonstrated positive beneficial effects on knee pain, improved physical function, and increased medial joint space width (mJSW) at 52 weeks in key subgroups of subjects with knee osteoarthritis (OA) compared to placebo (PBO). A 24-week phase 2b study was conducted to refine patient reported outcome (PRO) measures, target population, medication dose, and to evaluate safety. PRO results for Weeks 12 and 24 are presented here. Methods: Subjects had ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2-3, Pain Numeric Rating Scale (NRS) score ≥4 and ≤8 in the target knee and <4 in the contralateral knee. A single IA injection of 2 mL SM04690 (0.03, 0.07, 0.15 or 0.23 mg), vehicle PBO, or sham (dry needle only) was given in the target knee at baseline. PRO endpoints included change from baseline in weekly average of daily pain in the target knee by NRS diary (NRS [0-10]), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain [0-100], WOMAC Physical Function [0-100], and Patient Global Assessment (PtGA) (VAS [0-100]). This study was not formally powered, and sample size was based upon accepted dose-finding convention. Results: 695 subjects (mean age 59.0 [±8.5] years, BMI 29.0 [±4.0] kg/m2, female 58.4%, KL3 57.3%) were enrolled and dosed; 635 (91.4%) completed the study. No meaningful differences in incidence of adverse events were seen between treatment and control groups. In the ‘full analysis set’ (all randomized, dosed subjects), significant improvements from baseline compared with PBO were observed in pain NRS for 0.07 mg (Week 12 [P=0.001], Week 24 [P=0.031]) and 0.23 mg (Week 12 [P=0.012], Week 24 [P=0.022]) SM04690 dose groups (Figure). Similar improvements were observed in WOMAC Pain for 0.07 mg (Week 12 [P=0.04]) and 0.23 mg (Week 12 [P=0.003], Week 24 [P=0.031]) dose groups. For WOMAC Physical Function, improvements were observed for 0.07 mg (Week 12 [p=0.021]) and 0.23 mg (Week 12 [p=0.006], Week 24 [P=0.017]) dose groups. PtGA improvements were observed for 0.07 mg (Week 12 [P=0.031]), and 0.23 mg (Week 12 [P=0.010], Week 24 [P=0.033]) dose groups. Conclusions: SM04690, in development as a potential disease modifying OA drug, showed in this phase 2b study statistically significant improvements from baseline in both the 0.07 mg and 0.23 mg dose groups compared with PBO for Pain NRS, WOMAC Pain, WOMAC Physical Function, and PtGA. These data support the continued development of SM04690 as a potential treatment for knee OA. Phase 3 studies are being planned. Figure. Actual observations over time and ladder plots depicting mean improvement (± 95% CI) of SM04690 compared with placebo adjusted for baseline for Pain NRS.

Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo

BackgroundSprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential disease-modifying osteoarthritis drug (DMOAD). In vitro studies have shown that cartilage regenerative properties of sprifermin involve chondrocyte proliferation and extracellular matrix (ECM) production. To gain further insight into the process of sprifermin in the cartilage tissue, this study aimed at investigating the ECM turnover of articular cartilage explants in a longitudinal manner.MethodsBovine full-depth articular cartilage explants were stimulated with sprifermin or placebo at weekly intervals, similar to the dosing regimen used in clinical trials. Pre-culturing with oncostatin M and tumour necrosis factor-α, was also used to induce an inflammatory state before treatment. Metabolic activity was measured using AlamarBlue, and chondrocyte proliferation was visualized by immuno-histochemical detection of proliferating cell nuclear antigen. ECM turnover was quantified by biomarker ELISAs; ProC2 reflecting type II collagen formation, CS846 reflecting aggrecan formation, active MMP9, C2M and AGNx2 reflecting matrix metalloproteinase activity, and AGNx1 reflecting aggrecanase activity.ResultsSprifermin was able to reach the chondrocytes through the extracellular matrix, as it increased cell proliferation and metabolic activity of explants. ProC2 and CS846 was dose-dependently increased (P < 0.05) by sprifermin compared to placebo, while C2M and AGNx2 were unaffected, active MMP9 was slightly decreased, and AGNx1 was slightly increased. Over the course of treatment, the temporal order of ECM turnover responses was AGNx1, then ProC2, followed by CS846 and MMP9. Pro-inflammatory activation of the explants diminished the ECM turnover responses otherwise observed under non-inflammatory conditions.ConclusionsThe data suggest that sprifermin has chondrogenic effects on articular cartilage ex vivo, exerted through a sequential process of ECM turnover; aggrecan degradation seems to occur first, while type II collagen and aggrecan production increased at a later time point. In addition, it was observed that these chondrogenic effects are dependent on the inflammatory status of the cartilage prior to treatment.

EULAR 2017: Annual European Congress of Rheumatology, June 14–17, 2017, Madrid, Spain

EULAR 2017: Annual European Congress of Rheumatology, June 14–17, 2017, Madrid, Spain