Objective: To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/ GLPG1972 for the treatment of symptomatic knee osteoarthritis. Design: ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75,150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. Results: Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. Conclusions: Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis. & COPY; 2023 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: The ROCCELLA study is a large multi-centre, randomized, double-blind, placebo-controlled clinical trial that was conducted at 107 sites in Europe, Asia, and North- and South-America (clinicaltrials.gov: NCT03595618). It was designed to test the safety and efficacy of a disease modifying osteoarthritis drug (DMOAD) candidate that inhibits ADAMTS-5 (GLPG1972/S201086). The study population was enriched with structural progressors of knee OA, by including knees with presence of baseline medial radiographic OARSI atlas joint space narrowing [JSN] grade 1 or 2, and certain levels of pain (VAS 40-90/100mm). The primary endpoint was the longitudinal change (over up to one year) in central medial femoro-tibial (cMFTC) cartilage thickness, measured by MRI. As this was a clinical study that involved a large number of centers, it was deemed important to evaluate the test-retest reliability of the primary endpoint and other structural measures, as well as the smallest detectable change (SDC) threshold at which progression can be assumed to have occurred with 95% confidence in single cases. The objective of this analysis is thus to assess the test-retest reliability with repositioning of the knee at baseline as well as at 12-month follow-up, a prerequisite for computing the SDC. Methods: The study included 932 participants (231-234 in each of four treatment groups). Of these, 841 study participants had baseline and at least one longitudinal follow up MRI measurement, 586 at 1.5 Tesla (T), and 255 at 3.0 T across 98 MRI sites. These included magnets from several vendors (Siemens, GE, and Philips). Of the 841 participants, 69 (52 x 1.5T; 17 x 3T) had test-retest at baseline (across 65 sites), and 47 (37 x 1.5T; 10 x 3T) had test-retest at baseline as well as at 12-month follow-up (across 46 sites). Sagittal spoiled gradient echo MRI sequences with fat suppression or water excitation (slice thickness 1.5 mm, in plane resolution 0.31 mm) were acquired. Femorotibial cartilage thickness was analyzed from experienced readers using proprietary software (Chondrometrics GmbH, Ainring, Germany). The MRIs for each participant knee were read by the same reader in one reading session, with full blinding to test-retest status and time point (two baseline, one 6-month, and two 12-month MRIs in one set). Test-retest reliability was expressed as the root mean square (RMS) standard deviation (SD) and coefficient of variation (CV%). The SDC was computed from the 1.96-fold SD of the differences between the 1-year change in the test acquisitions, and 1-year change in the retest acquisitions, according to published literature. The SDC analysis was limited to measure of the medial femorotibial compartment (MFTC), as the participants had medial compartment disease. Results: The test-retest reliability and SDC for the medial compartment structural MRI measures are shown in Table 1. These were similar at baseline and at 12-month follow up. The baseline test-retest variability for the 47 knees that also had 12-month follow-up was very similar to that in the 69 baseline knees (data not shown). The errors (CV%) were somewhat larger for the small central subregion (cMFTC) than for the total compartment, and were similar between the tibia and the femur (Table 1). There was no obvious relationship between the magnitude of the test-retest errors and the baseline cartilage thickness (Fig. 1). The reliability results for the lateral compartment and total femorotibial joint are shown in Table 2 for comparison. The RMS SD was observed to be similar to the medial compartment measures, whereas the CV% values were smaller due to the greater baseline cartilage thickness in the lateral than medial compartment. Conclusions: To our knowledge, this is the first study to report test-retest reliability of structural measures of cartilage thickness from MRI, obtained within a large multi-center clinical trial at both baseline and follow-up, and to report SDC thresholds obtained within a DMOAD trial. This trial covered almost 100 sites, including 1.5 and 3.0 T magnets from three different vendors, of which about two thirds had test-retest acquisitions at baseline, and about half also at follow-up. The present analysis did not stratify the results by placebo and treatment groups. As observed previously, test-retest errors were somewhat greater for smaller subregions (e.g. cMFTC) than for the total compartment (MFTC); they were in the same range in this large multi-center clinical trial as in previously published single-center or smaller multi-center studies. There were no obvious differences in reliability between the tibia and femur, or between the medial and lateral compartment. Further, there was no dependence of the test-retest errors on the absolute baseline thickness measures. This analysis reports the SDC for this trial as a study-specific threshold that can be applied to discern progressor from non-progressor knees. When striving for a 95% confidence level in each single case, the SDC assumes a value of 8.8% for the primary endpoint, which is very close to the progressor threshold used in this trial (8%), obtained a priori, employing a different approach. In summary, the results confirm a high test-retest reliability for quantitative cartilage morphometry in a large multi-vendor clinical trial with almost 100 sites at both baseline and follow-up. The technology used thus appears robust and can be used to measure structural progression of disease in large multi-center multi-vendor clinical trials with high precision.

Purpose: To date, no disease-modifying osteoarthritis drugs (DMOADs) have been approved for the treatment of knee osteoarthritis (OA). S201086/GLPG1972 is a potent and selective inhibitor of ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motif-5) in development as a DMOAD, hypothesized to reduce cartilage loss via inhibition of the enzymatic cleavage of aggrecan (a key component of cartilage). S201086/GLPG1972 has been shown to reduce cartilage degradation in preclinical models of OA. Therefore, we aimed to evaluate the efficacy and safety of S201086/GLPG1972 in patients with knee OA. Methods: ROCCELLA was a randomized, placebo-controlled, dose-ranging, phase 2 study comprising a 5-week screening period, a 52-week double-blind treatment period and a 2-week safety follow-up period (ClinicalTrials.gov ID: NCT03595618). Patients aged 40-75 years with knee OA and pain severity in the target knee of 40-90 mm on a visual analog scale at screening and baseline were included. Target knees had predominant medial compartment disease, with Kellgren-Lawrence (KL) grade 2 or 3 and OARSI medial joint space narrowing (JSN) grade 1 or 2. Patients were randomized 1:1:1:1 to placebo or 75 mg, 150 mg or 300 mg S201086/GLPG1972 administered orally once daily. Concomitant analgesics (non-steroidal anti-inflammatory drugs and acetaminophen) were permitted. The primary endpoint was change from baseline to week 52 in cartilage thickness of the central medial femorotibial compartment (cMFTC) of the target knee, as measured by quantitative magnetic resonance imaging (qMRI) and analyzed by a central reading facility. Secondary efficacy endpoints included: change from baseline to week 52 in radiographic joint space width of the target knee (JSW; X-ray with central readout); patient-reported outcomes (including WOMAC scores, patient global assessment [PGA] score and pain score, both measured by visual analog scales); and safety outcomes. A mixed-effects model for repeated measures (using all longitudinal observations at each post-baseline visit) was used for the primary analysis. Results: Across 12 countries, 3319 patients were screened and 932 were included in the study. Patients had a mean age of 62.9 years and the majority (69.3%) were women. Baseline characteristics were similar across study groups (Table 1). Overall, 88.8% of knees were KL grade 3 and 67.3% were OARSI medial JSN grade 2. Patients experienced substantial cartilage loss; the mean (SD) change in cMFTC cartilage thickness was −0.12 (0.27) mm from baseline to week 52 in the placebo group. However, no statistically significant differences between treatment groups and placebo were observed for the primary endpoint of cMFTC cartilage thickness loss (placebo vs 75 mg, p = 0.165; vs 150 mg, p = 0.939; vs 300 mg, p = 0.682; Figure 1). These results were confirmed by sensitivity analyses assessing the management of missing data and delayed week 52 qMRI owing to the COVID-19 pandemic. No significant differences between treatment groups and the placebo group were observed at any time point in any of the secondary endpoints, including changes in WOMAC total score and subscores (Figure 2), radiographic JSW, PGA score or pain score. Treatment-emergent adverse events (TEAEs) and serious adverse events were experienced by similar proportions of patients in the placebo and S201086/GLPG1972 groups (Table 2). The most common TEAEs across all S201086/GLPG1972 treatment groups were arthralgia, nasopharyngitis and fall (Table 2). Tolerability was similar across the three S201086/GLPG1972 dose groups, with 6.8% (75 mg) to 8.6% (300 mg) of patients withdrawing from treatment owing to TEAEs, compared with 3.8% in the placebo group. Conclusions: The study successfully selected patients who experienced a substantial decrease in cartilage thickness over 52 weeks; a decrease that would be large enough to demonstrate a sizeable structural benefit of a DMOAD candidate. However, the study failed to meet its primary endpoint (change from baseline to week 52 in cartilage thickness of the cMFTC) and secondary endpoints, and there was no dose-response relationship. S201086/GLPG1972 had a good safety profile and was generally well tolerated.Figure 2Change over time in WOMAC subscores. Data show mean and standard error. W, week.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Baseline patient demographics and characteristics.Demographic/characteristicPlacebo (n = 234)S201086/GLPG197275 mg (n = 234)S201086/GLPG1972150 mg (n = 231)S201086/GLPG1972300 mg (n = 232)Age (years), mean (SD)63.3 (7.1)62.9 (7.5)63.2 (7.2)62.1 (7.4)Age (years), n (%)-40-5528 (12.0)31 (13.2)29 (12.6)33 (14.2)55-6595 (40.6)94 (40.2)96 (41.6)97 (41.6)≥ 65111 (47.4)109 (46.6)106 (45.9)103 (44.2)Women, n (%)163 (69.7)164 (70.1)165 (71.4)154 (66.1)Race, n (%)White171 (73.1)167 (71.4)177 (76.6)168 (72.1)Black or African American25 (10.7)27 (11.5)19 (8.2)25 (10.7)Asian32 (13.7)31 (13.2)28 (12.1)30 (12.9)American Indian, native Alaskan, or native Hawaiian or other Pacific Islander01 (0.4)1 (0.4)2 (0.9)Multiple6 (2.6)8 (3.4)6 (2.6)8 (3.4)Time since first diagnosis (years), mean (SD)7.3 (6.7)6.9 (6.4)7.6 (7.4)7.1 (7.2)KL grade, n (%)229 (12.4)15 (6.4)30 (13.0)29 (12.4)3205 (87.6)219 (93.6)200 (86.6)204 (87.6)4001 (0.4)0OARSI atlas JSN grade, n (%)001 (0.4)1 (0.4)0170 (29.9)74 (31.6)73 (31.6)84 (36.1)2164 (70.1)159 (67.9)156 (67.5)148 (63.5)3001 (0.4)1 (0.4)Cartilage thickness in cMTFC, mean (SD)3.19 (0.82)3.25 (0.76)3.23 (0.76)3.33 (0.80)Joint space width, mean (SD)2.48 (0.86)2.5 (0.78)2.5 (0.78)2.58 (0.84)cMTFC, central medial femorotibial compartment; JSN, joint space narrowing; KL, Kellgren-Lawrence; SD, standard deviation. Open table in a new tab Table 2Summary of safety outcomes.Events, n (%)Placebo (n = 234)S201086/GLPG197275 mg (n = 234)S201086/GLPG1972150 mg (n = 231)S201086/GLPG1972300 mg (n = 232)TEAEs174 (74.4)174 (74.4)177 (76.6)174 (75.0)Severe TEAEs29 (12.4)25 (10.7)27 (11.7)30 (12.9)Treatment-related TEAEs37 (15.8)36 (15.4)30 (13.0)47 (20.3)Serious TEAEs18 (7.7)17 (7.3)17 (7.4)18 (7.8)Serious treatment-related TEAEs2 (0.9)02 (0.9)1 (0.4)TEAEs leading to drug withdrawal9 (3.8)16 (6.8)17 (7.4)20 (8.6)TEAEs occurring in ≥ 5% of patientsArthralgia19 (8.1)27 (11.535 (15.2)26 (11.2)Nasopharyngitis20 (8.5)21 (9.0)16 (6.9)22 (9.5)Fall13 (5.6)15 (6.4)20 (8.7)16 (6.9)Back pain19 (8.1)11 (4.7)10 (4.3)7 (3.0)Headache9 (3.8)15 (6.4)12 (5.2)11 (4.7)Hypertension16 (6.8)6 (2.6)9 (3.9)12 (5.2)Osteoarthritis10 (4.3)8 (3.4)12 (5.2)11 (4.7)Increased blood creatine phosphokinase8 (3.4)12 (5.1)7 (3.0)9 (3.9)Upper respiratory tract infection10 (4.3)7 (3.0)12 (5.2)6 (2.6)Increased gamma-glutamyltransferase4 (1.7)3 (1.3)2 (0.9)16 (6.9)TEAE, treatment-emergent adverse event. Open table in a new tab cMTFC, central medial femorotibial compartment; JSN, joint space narrowing; KL, Kellgren-Lawrence; SD, standard deviation. TEAE, treatment-emergent adverse event.

Purpose: Osteoarthritis (OA) is characterized by structural changes of the joint, of which loss of articular cartilage is one of the major signs. The main proteoglycan component of the extracellular matrix of articular cartilage is aggrecan. ADAMTS-5, A Disintegrin And Metalloproteinase with ThromboSpondin-motif-5, is a key aggrecan-cleaving enzyme involved in cartilage degradation, resulting in ARGS-aggrecan neo-epitope levels measurable in synovial fluid and serum. GLPG1972/S201086 is a highly specific and potent ADAMTS-5 inhibitor in development as an orally administered DMOAD candidate. Clinical Phase 1 studies demonstrated favorable pharmacokinetics and a strong and consistent target engagement in exposed healthy subjects as well as in OA patients. A pooled Phase 1 safety analysis (171 exposed subjects) showed that GLPG1972/S201086 was generally safe and well tolerated. Here we present the study design of a large Phase 2 clinical trial in knee OA (KOA) patients. Methods: This multi-center, randomized double-blind placebo-controlled trial is conducted in 107 sites in Europe, Asia and North- and South-America. Total study duration is around 59 weeks (5-weeks screening, 52-weeks treatment and 2-weeks follow-up) with 10 visits scheduled. Patients (male/female of non-childbearing potential) aged [40-75] years with a diagnosis of primary femorotibial KOA according to the ACR clinical and radiologic criteria were screened. Exclusion criteria targeted specific KOA-, general health- and drug-drug interaction related confounding and risk factors. Knees with a pain score [40-90] mm on a 100 mm Visual Analogue Scale (VAS) from eligible patients at screening were selected as potential target knee based on predominant medial compartment radiographic disease and KOA radiologic severity assessed by fixed flexion weight-bearing X-ray. In order to ensure sufficient levels of structural progression (cartilage loss) in the sample, potential target knees had to meet the combined Kellgren/Lawrence (KL) 2 or 3 and OARSI medial joint space narrowing (JSN) 1 or 2 severity grading range upon central reading of the X-ray. If both knees were eligible, the target knee was selected based first on the highest KL grade, then on the highest JSN grade and finally on the highest pain VAS score at baseline. Patients were randomized 1:1:1:1 to take placebo or GLPG1972/S201086 (at three different dose levels) orally once daily for 52 weeks. After confirmation of the patient's eligibility, MRI of the target knee is performed at baseline visit, week 28 and week 52, or at the withdrawal visit (WD). A central medical imaging vendor is in charge of qualifying, training and QC of MRI acquisition for all investigational sites. MRI read-out will be performed centrally by an MRI analysis vendor. Assessment of the central medial tibio-femoral compartment (cMTFC) cartilage thickness of the target knee at baseline and at week 52 will determine the primary endpoint. Secondary objectives are safety and tolerability by assessing vital signs and treatment emergent (serious) adverse events, central lab and centrally read 12-lead ECG parameters. Additional secondary structural and clinical efficacy objectives are based on changes from baseline in the target knee: cartilage thickness and bone area on qMRI, KOA "progressor" rates, Joint Space Width on X-ray, pain VAS, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total and sub scores, Patient Global Assessment VAS and the proportion of Outcome Measures in Rheumatology (OMERACT)-OARSI responders. VAS and WOMAC scores are captured digitally (ePRO). Blood samples are taken at specified time points to assess pharmacokinetics of the investigational drug and its potential metabolites. Exploratory analyses of e.g. biochemical biomarkers of cartilage and bone turn-over in serum and/or urine are planned as well. A sample size of 213 per treatment arm was calculated to allow a robust demonstration of primary endpoint. Adequate methodology has been set up to maintain the experiment wise type I error at 5%. A Mixed-effects Model for Repeated Measures will be used for the primary analysis. The randomisation was stratified by geographic region. Results: The study started in August 2018 and was fully recruited (N=938) by June 2019. Large numbers of patients with KOA had to be screened to meet the stringent pre-specified selection criteria. The study completion is expected by end of 2020. Conclusions: This is the first international Phase 2 study where patients with primary KOA are treated for 52 weeks with GLPG1972/S201086, an orally administered DMOAD candidate. This clinical trial was designed with a combination of two radiologically-based selection criteria to ensure sufficient levels of structural progression (cartilage loss) in the study population.

Background: Osteoarthritis (OA) is a degenerative joint disease involving structural pathology of all joint tissues, and most commonly affecting the knee, hip and hand. Degradation of the cartilage extracellular matrix represents a central feature of OA and is widely thought to be mediated by proteinases that degrade primarily aggrecan and collagen. ADAMTS-5, a Disintegrin And Metalloproteinase with ThromboSpondin-motif-5, is a key aggrecan-cleaving enzyme involved in cartilage degradation. S201086/GLPG1972, a potent and highly selective inhibitor of ADAMTS-5, is an oral Disease-Modifying OsteoArthritis Drug (DMOAD) candidate. Objectives: The primary objective of the ROCCELLA phase 2 clinical trial ( NCT03595618 ) is to evaluate the effect of S201086/GLPG1972 over 52 weeks of treatment (3 dose groups compared to placebo) in reducing cartilage loss. Cartilage thickness of the knee is being measured quantitatively by Magnetic Resonance Imaging. Here, we describe the baseline characteristics of patients included in the ROCCELLA clinical trial. Methods: The main inclusion criteria were: male or female, aged 40 to 75, with a diagnosis of knee OA according to the clinical and radiological criteria of the American College of Rheumatology. The target knee had to meet a pain score between 40 and 90 mm on a 100 mm Visual Analog Scale (VAS), and the following radiographic feature upon central radiographic readings: Kellgren/Lawrence (KL) 2 or 3 and OARSI medial joint space narrowing (JSN) 1 or 2 (for more details see Deckx et al . OARSI 2020). The rationale for these specific radiographic inclusion criteria was to ensure sufficient cartilage loss over 12 months to assess the efficacy of S201086/GLPG1972. Results: Across 12 countries, 3319 patients were screened and 932 were finally included in the study. The screen failure of 72% is mainly due to the radiological criteria. The age of the patients was 62.9 ± 7.3 years (mean ± SD) with a majority of women (69.3%). The BMI was 30.5 ± 4.7 kg/m 2 . The duration of knee OA was 7.2 ± 6.9 years. Five hundred and one (53.8%) patients reported a medical history of musculoskeletal and connective tissue disorders, mainly osteoarthritis in other sites (20.2%), back pain (13.6%), and arthralgia (9.8%). At inclusion, 97.2% of the patients were taking different types of drug treatments, mainly anti-inflammatory and anti-rheumatic products (69.4%) and analgesics (42%). At baseline, 11% of the target knees were KL2 and 89% were KL3; 32% were OARSI medial JSN grade 1 and 68% grade 2. Target knees at inclusion had a pain score on the VAS of 63.5 ± 11.4 mm (range 0-100, with 0 for no and 100 for extreme pain) and a total WOMAC (Likert 3.1) score of 48.0 ± 15.0 (range 0-96). The WOMAC subscores for pain, stiffness and physical function were 10.0 ± 3.2 (range 0-20), 4.2 ± 1.6 (range 0-8) and 33.8 ± 11.2 (range 0-68, indicating functional limitation), respectively. Conclusion: For this clinical trial, patients were selected to present radiological criteria ( i.e. OARSI JSN 1 and 2) to ensure sufficient structural progression (cartilage loss) over 12 months, as well as clinical symptoms. These stringent selection criteria were the main cause for the high screen failure rate. These baseline characteristics should warrant the ability to evaluate the efficacy of S201086/GLPG1972 as a DMOAD candidate. The search for an effective pharmacological treatment that can prevent or cure OA remains a major challenge and unmet medical need. Disclosure of Interests: Katy Bernard Employee of: Institut de Recherches Internationales Servier, Sergey GRANKOV Employee of: Institut de Recherches Internationales Servier, Marjolijne van der Stoep Employee of: Galapagos, Agnès Lalande Employee of: Institut de Recherches Internationales Servier, Olivier Imbert Employee of: Institut de Recherches Internationales Servier, De Phung Employee of: Galapagos, Damien Chimits Employee of: Institut de Recherches Internationales Servier, Karine Muller Employee of: Galapagos, Ellen van der Aar Employee of: Galapagos, Henri Deckx Employee of: Galapagos, Maria Pueyo Employee of: Institut de Recherches Internationales Servier, Felix Eckstein Grant/research support from: Merck, Orthotrphix, Servier, Galapagos, Kolon Tissuegene, Samumed, Novartis, Consultant of: Merck, Bioclinica, Servier, Samumed, Roche, Kolon Tissuegene, Galapagos and Novartis, Employee of: co-owner and employment with Chondrometrics