BACKGROUND:Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE). METHODS:Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score. The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis. Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. FINDINGS:Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively. INTERPRETATION:In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. FUNDING:Merck Healthcare (Darmstadt, Germany).

BACKGROUND:Toll-like receptor (TLR)7 and TLR8 are nucleic-acid sensors involved in lupus pathogenesis. We aimed to investigate the efficacy and safety of enpatoran, an oral small-molecule TLR7/8 inhibitor, in participants with active skin manifestations of cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). METHODS:WILLOW is a phase 2, randomised, double-blind, placebo-controlled, basket, dose-finding study conducted across 132 centres in 22 countries, enrolling patients into two cohorts (A and B) with different eligibility criteria. In Cohort A of the trial, we enrolled participants aged 18-75 years who had CLE only or SLE with mild or no extra-mucocutaneous disease activity (British Isles Lupus Assessment Group [BILAG]-2004 scores 1B, C, or D), and a Cutaneous Lupus Disease Area and Severity Index-activity (CLASI-A) score of 8 or higher. Participants were randomised (1:1:1:1) to receive placebo or enpatoran at a dose of 25 mg, 50 mg, or 100 mg twice per day for 24 weeks, in combination with standard of care. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on the percentage change from baseline in CLASI-A total score at week 16, analysed with a multiple comparison procedure-modelling approach. Efficacy analyses were done in the full analysis set of all randomly allocated participants. Safety was assessed in all patients who received at least one dose of study treatment. There was no involvement of people with lived experience of CLE or SLE in study design. This trial is registered with ClinicalTrials.gov (NCT05162586; completed); results from Cohort B will be reported separately. FINDINGS:Between May 4, 2022, and Feb 6, 2024, 463 patients were screened for eligibility across cohorts A and B; 102 participants were randomly assigned within Cohort A and received treatment (safety population). Two participants (n=1 each from the enpatoran 25 mg and 50 mg groups) were randomly allocated to Cohort A but were subsequently found to have had BILAG scores ≥1A and 2B at screening and were therefore deemed ineligible and excluded; thus 100 participants were analysed for efficacy (placebo group n=26; enpatoran 25 mg group n=23; enpatoran 50 mg group n=25; enpatoran 100 mg group n=26). Participants in the full analysis set had a median age of 47 years (IQR 36-55); 77 (77%) were female, 23 (23%) were male, and 48 (48%) were White. At week 16, enpatoran had a significant, dose-dependent effect on CLASI-A score, with adjusted mean changes from baseline of -64 percentage points (95% CI -70 to -58) in the enpatoran 25 mg group, -68 percentage points (-75 to -61) in the enpatoran 50 mg group, and -72 percentage points (-80 to -64) in the enpatoran 100 mg group, versus -44 percentage points (-55 to -33) in the placebo group (p=0·0002 for dose-response relationship). The most common treatment-emergent adverse event was upper respiratory tract infection, which occurred in two (8%) of 24 patients in the enpatoran 25 mg group, four (15%) of 26 in the enpatoran 50 mg group, five (19%) of 26 in the enpatoran 100 mg group, and two (8%) of 26 in the placebo group. Overall, one (4%) participant in the placebo group, one (4%) in the enpatoran 100 mg group, and two (8%) in the enpatoran 25 mg group had serious adverse events; none were reported with enpatoran 50 mg. INTERPRETATION:Enpatoran showed a significant and dose-dependent effect on disease activity in participants with active cutaneous manifestations of CLE or SLE, and was well tolerated. FUNDING:Merck Healthcare KGaA, Darmstadt, Germany.

O010 / #827 Topic:AS07 - Cutaneous Lupus Late-Breaking Abstract ABSTRACT CONCURRENT SESSION 01: FINDINGS FROM LUPUS CLINICAL TRIALS 22-05-2025 1:40 PM - 2:40 PM No treatment is approved for cutaneous lupus erythematosus (CLE), which may occur in the presence or absence of systemic lupus erythematosus (SLE). Enpatoran is an oral small molecule toll-like receptor 7/8 inhibitor, with potential to modulate processes central to CLE and SLE pathophysiology. WILLOW (NCT05162586) is a Phase II randomized double-blind placebo-controlled dose-finding parallel adaptive study in adults with SLE or CLE receiving standard of care to evaluate the efficacy and safety of enpatoran. WILLOW Cohort A enrolled patients with CLE or SLE who had active lupus rash. Patients with Cutaneous Lupus Disease Area and Severity Index-Activity (CLASI-A) score ≥ 8 CLE were enrolled; they had CLE only, or SLE with mild or no extramucocutaneous disease activity [British Isles Lupus Assessment Group 2004 < 1B, C, D]). Patients were randomized 1:1:1:1 to 1 of 3 doses of enpatoran or placebo for 24 weeks, with an additional 2-week safety follow-up for patients not choosing to enter the long-term extension. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on change from baseline in CLASI-A score at Week 16. Secondary endpoints included change from baseline in Physician’s Global Assessment at Weeks 16 and 24, clinically meaningful corticosteroid (CS) reduction, and occurrence of Cutaneous Lupus Activity-Investigator Global Assessment 0 or 1 at Week 16 and Week 24. Exploratory endpoints included CLASI-A improvement ≥ 50%/70% (CLASI-50/70). Treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of special interest and laboratory parameters were collected from Day 1 to the end of safety follow-up. 102 patients were randomized, and 100 patients were included for efficacy evaluation (placebo n = 26; enpatoran low dose n = 23; mid dose n = 25; high dose n = 26). 77.0% of patients were female, and 58.0% had CLE only. At baseline, 59.0% of patients were receiving systemic CS, 38.0% immunosuppressants and 76.0% antimalarials; 71% had moderate-to-severe disease (CLASI-A ≥ 10). The primary outcome was achieved. At Week 16, a significant dose response for enpatoran in reducing CLASI-A from baseline was detected (p = 0.0002) (Table 1). Table 1 Dose-response relationship of enpatoran in reducing disease activity based on change from baseline in CLASI-A score at Week 16 (FAS; N = 100) Furthermore, up to 91.3% of patients receiving enpatoran achieved CLASI-50, and up to 60.9% achieved CLASI-70 at Week 16, compared with 38.5% and 11.5% of patients, respectively, receiving placebo. Enpatoran was well tolerated across all study doses. High-dose enpatoran was associated with a higher rate of TEAEs (Table 2) than lower doses or placebo; the most frequently reported TEAEs were infections and infestations. Table 2 Treatment-emergent adverse events (SAS; N = 102) Enpatoran demonstrated a significant dose response in change from baseline in CLASI-A compared with placebo at Week 16 in patients with CLE or SLE and was well tolerated.Acknowledgments:The authors wish to thank Dominika Weinelt for their support with the study conduct and analysis. Medical writing support was provided by Nicole Jones on behalf of Amica Scientific, Macclesfield, UK, and sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany.

Objective To assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple injections of M6495, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS‐5) nanobody, in healthy volunteers and patients with osteoarthritis. Methods Two randomized, placebo‐controlled, double‐blind studies were performed. Study 1 enrolled 54 healthy male volunteers who received one subcutaneous (s.c.) injection of M6495 (1‐300 mg) or placebo (ratio 2:1), evaluating safety, PK, and PD as changes in the serum aggrecan fragment alanine‐arginine‐glycine‐serine (ARGS). Study 2 enrolled 32 patients with osteoarthritis with Kellgren–Lawrence grades 2 to 4 and pain greater than or equal to 40 on the Western Ontario and McMaster Universities Arthritis Index pain subscale at screening and evaluated the safety, PK, and PD of three doses every two weeks (75‐300 mg per dose) or six once‐weekly M6495 s.c. doses (300 mg) or placebo (ratio 3:1) over 106 days’ follow‐up. Results M6495 in single and multiple doses of less than or equal to 300 mg s.c. weekly was well tolerated with no clinically significant changes in any safety parameter. Adverse events more frequently reported in the M6495 groups were mostly mild cases of injection site reactions, myalgia, and nausea, which resolved after treatment cessation. The elimination half‐life of single s.c. doses of M6495 ranged from 79 to 267 hours. M6495 administration substantially reduced serum ARGS levels, indicative of target engagement and indicating disease‐modifying potential of M6495. Conclusion Treatment with M6495 in single and multiple doses up to and including 300 mg s.c. was found to be well tolerated and adequately safe for further clinical evaluation of potential disease‐modifying effects.

Background Aberrant toll-like receptor (TLR) 7/8 activation is thought to be involved in both lupus pathogenesis and glucocorticoid resistance. Enpatoran, a selective and potent dual inhibitor of TLR7/8 that is in development for cutaneous and systemic lupus erythematosus (CLE/SLE), was well tolerated by healthy participants and patients hospitalized with COVID-19 pneumonia. We report evaluation of the glucocorticoid-sparing effect of enpatoran and a trial design to assess its efficacy and safety in patients with SLE and/or CLE. Methods Cytokine concentrations and gene expression changes were measured in stimulated human peripheral blood mononuclear cells (PBMCs) from healthy donors after treatment with dexamethasone, TLR7/8 inhibitor, or both. A Phase II basket design, proof-of-concept, dose-finding, randomized, double-blind, placebo-controlled 24-week study in patients with SLE and/or CLE (WILLOW; NCT05162586), which will also assess glucocorticoid sparing, was designed. Results In healthy donor PBMCs, synergy was observed between TLR7/8 inhibitor and dexamethasone. Combination treatment inhibited cytokine release (interleukin-6) with greater potency than either treatment alone and reduced the expression of nuclear factor-kappa B and interferon-regulated genes. Glucocorticoid sparing will be evaluated by a mandatory tapering schedule in the WILLOW study, which has two cohorts (figure 1). Cohort A will enroll patients with CLE or SLE with predominantly active lupus rash. Cohort B, in two parts, will enroll SLE patients with moderate-to-severe systemic disease activity; Part 1 will assess clinical signal and Part 2 may be adapted to improve dose finding. The primary objectives are to evaluate the dose-response relationship of enpatoran in reducing disease activity based on CLASI-A or BICLA. The secondary objectives include evaluating effects on disease control and clinically meaningful glucocorticoid reduction. Conclusions Enpatoran is a novel TLR7/8 inhibitor and may enable glucocorticoid dose reduction in patients with SLE and CLE. The WILLOW study incorporates multiple novel elements including a basket design and evaluation of glucocorticoid sparing.

Abstract Enpatoran is a selective inhibitor of toll‐like receptors 7 and 8 (TLR7/8) that potentially targets pro‐inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID‐19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9‐point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9‐point scale ≤3). Clinical deterioration (WHO 9‐point scale ≥ 5) was a key secondary objective. Treatment‐emergent adverse events (TEAEs) were comparable across groups (56.5%–63.0%). Treatment‐related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4–3.9 days across groups, with placebo‐treated patients recovering on average faster than anticipated. Clinical deterioration event‐free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID‐19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity.

OBJECTIVE:To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin. METHODS:Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40-90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint. RESULTS:The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07]). CONCLUSIONS:Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials. CLINICAL TRIAL REGISTRATION:NCT01919164.

Objective The 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, we report 5-year efficacy and safety results. Methods Patients were randomised to intra-articular sprifermin 100 mu g or 30 mu g every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression. Results 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 mu g q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved similar to 50% from baseline in all groups. No patient in the 100 mu g q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 mu g q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53). Conclusion In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.

Osteoarthritis (OA) is a common disease worldwide with large unmet medical needs. To bring innovative treatments to OA patients, we at Merck have implemented a comprehensive strategy for drug candidate evaluation. We have a clear framework for decision-making in our preclinical pipeline, to design our clinical proof-of-concept trials for OA patients. We have qualified our strategy to define and refine dose and dosing regimen, for treatments administered either systemically or intra-articularly (IA). We do this through preclinical in vitro and in vivo studies, and by back-translating results from clinical studies in OA patients.

Background Results from the 5-year Phase II FORWARD study showed significant dose-dependent modification of total femorotibial joint (TFTJ) cartilage thickness change with sprifermin at 2 and 3 years, by quantitative MRI. Total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores improved by ∼50% in all treatment groups, including placebo (PBO). Selection of a patient (pt) subgroup with higher pain scores and lower joint space width (JSW) at baseline (BL), to identify pts who are at risk of further structural and symptomatic progression, may facilitate better WOMAC discrimination. Objectives Post-hoc analysis to evaluate cartilage thickness changes and symptomatic outcomes in an “at risk” subgroup of pts (BL medial or lateral minimum [m]JSW 1.5–3.5 mm and BL WOMAC pain score of 40–90). Methods Pts in FORWARD were randomized 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo); 100 µg q12mo; 30 µg q6mo; 30 µg q12mo; and PBO. The treatment period was 2 years, with an extended follow up at 3 years. Post-hoc analysis was conducted in the “at risk” subgroup. Treatment effects were estimated using a repeated measures model, controlling for BL, treatment, time, country and treatment by time interaction. Linear dose-effect trend tests were performed exploratively at each timepoint. Confidence intervals (CIs) were adjusted for multiplicity of treatments using Dunnett adjustment. Results 161/549 (29%) pts met criteria for the “at risk” subgroup. In this subgroup, BL characteristics were balanced between treatment arms. Pts in the PBO arm had more cartilage loss at 2 and 3 years vs the modified intent-to-treat (mITT) PBO arm (mean change from BL in mm [SD]: Year 2 -0.05 [0.10] vs -0.02 [0.07]; Year 3 -0.07 [0.09] vs -0.05 [0.07]), but TFTJ net cartilage modification with sprifermin 100 µg q6mo vs PBO was similar (adjusted mean difference from PBO [95% CI] in the at risk subgroup vs the mITT group: Year 2 0.06 [0.01, 0.11] vs 0.05 [0.02, 0.08]; Year 3 0.05 [-0.01, 0.12] vs 0.05 [0.02, 0.09]). Having both medial or lateral mJSW 1.5–3.5 mm AND pain score ≥40 at BL led to greater differentiation in WOMAC total and pain scores for sprifermin 100 µg q6mo vs PBO than having either BL characteristic alone. At Year 3 (18 mos after last injection), the exploratory dose-effect trend test had a nominal p-value of <0.05 (Fig 1; Table 1). Conclusion Despite substantial structural and symptomatic progression in the “at risk” subgroup, structural improvement with sprifermin was maintained, and WOMAC score improvements vs PBO increased over time and were significant at Year 3. This supports further investigation of sprifermin as a potential disease-modifying osteoarthritis drug in a targeted population where structural improvement may translate into symptomatic benefit vs PBO within a reasonable timeframe. Disclosure of Interests Hans Gühring Employee of: Employee of Merck KGaA, Darmstadt, Germany, Jeffrey Kraines Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Flavie Moreau Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Benjamin Daelken Employee of: Employee of Merck KGaA, Darmstadt, Germany, Christoph Ladel Employee of: Employee of Merck KGaA, Darmstadt, Germany, Wolfgang Wirth Shareholder of: Shareholder of Chondrometrics GmbH, Ainring, Germany, Employee of: Employee of Chondrometrics GmbH, Ainring, Germany, Philip G Conaghan Consultant for: Flexion Therapeutics, AbbVie, Medivir, Merck Serono, Novartis, GlaxoSmithKline, Felix Eckstein Shareholder of: Shareholder of Chondrometrics GmbH, Consultant for: Consulting fees from Merck KGaA, Samumed LLC, Abbvie, Bioclinica, TissueGene, Servier, and Roche, Employee of: Employee of Chondrometrics GmbH, Marc Hochberg Shareholder of: BriOri Biotech, Theralogix LLC., Consultant for: Bristol Myers Squibb, Eli Lilly, EMD Serono, Novartis Pharma AG, Pfizer Inc., Samumed LLC, Symic Bio Inc., Theralogix LLC, TissueGene Inc., TLC Biopharmaceuticals, Inc., Zynerba, Galapagos, IQVIA, Hoffman LaRoche.

Background Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug (DMOAD). 2-yr results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial joints (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative (q)MRI.1 Objectives To determine whether qMRI findings from FORWARD (manual segmentation) could be reproduced in the same cartilage regions using an independent method (automated segmentation), on the same dataset/time period. Methods Pts were randomized 1:1:1:1:1 to: sprifermin 100 μg q6mo; 100 μg q12mo; 30 μg q6mo; 30 μg q12mo; and placebo (n=110/110/111/110/108).1 Cartilage thickness was assessed at baseline and 6, 12, 18, and 24 months using 1.5- or 3-Tesla MRI images, analyzed manually.1 The same images were analyzed by automated cartilage segmentation using active appearance models, a supervised machine learning method, to produce maps of cartilage thickness for weight-bearing femoral and tibial cartilage surfaces, subdivided into anatomical masks. Results were blinded for treatment and timepoint for both methods. No statistical comparisons between methods were conducted. Endpoints were change from baseline in: 1) cartilage thickness in the TFTJ, MFTC and LFTC, using regions duplicated based on published data;1 2) cartilage thickness in the central subregion of the medial and lateral tibia and femur (cMT, cMF, cLT, cLF [conventions used by the automated analysis investigators]). As in previous analyses, treatment effect was assessed by observed changes and adjusted using repeated ANCOVA on change from baseline, including treatment group, timepoint, and country as fixed factors, baseline value as covariate and treatment by timepoint as interaction. Results Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 yrs with sprifermin vs placebo for the TFTJ (overall treatment effect and dose response across all doses, both P<0.001), MFTC (P=0.004 and P=0.044), and LFTC (both P<0.001). Table 1 shows changes from baseline for sprifermin 100 μg q6mo and placebo. Statistically significant dose-dependent structural modification of cartilage over 2 yrs was observed for sprifermin vs placebo in the cMT (100 μg q6mo), cLT (100 μg q6mo, q12mo) and cLF (100 μg q6mo, q12mo). In the cMF, there was no treatment effect, but there was a linear trend for dose responsiveness. The results showed a consistent pattern to those obtained using manual segmentation. Conclusion Cartilage thickness assessed by automated segmentation provided a consistent pattern of structural modification in FORWARD compared with manual segmentation. This is the first time that two independent methods of image analysis have reached the same conclusions in an interventional DMOAD trial. The findings strengthen the conclusions that sprifermin modifies cartilage loss/structural progression in knee OA. References [1] Hochberg, et al. ACR 2017 Disclosure of Interests Alan Brett Employee of: Employee of Imorphics, Manchester, UK, Michael A Bowes Employee of: Employee of Imorphics, Manchester, UK, Philip G Conaghan Consultant for: Flexion Therapeutics, AbbVie, Medivir, Merck Serono, Novartis, GlaxoSmithKline, Christoph Ladel Employee of: Employee of Merck KGaA, Darmstadt, Germany, Jeffrey Kraines Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Hans Gühring Employee of: Employee of Merck KGaA, Darmstadt, Germany, Flavie Moreau Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Felix Eckstein Shareholder of: Shareholder of Chondrometrics GmbH, Consultant for: Consulting fees from Merck KGaA, Samumed LLC, Abbvie, Bioclinica, TissueGene, Servier, and Roche, Employee of: Employee of Chondrometrics GmbH