The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial

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

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

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 µg or 30 µg 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 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg 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 µg 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. Trial registration number NCT0191916

Second-line treatment in pancreatic cancer patients: Who profits? Results from the CONKO study group

OBJECTIVES: With increasing numbers of therapeutic options in inoperable pancreatic cancer (PAC), patients tend to receive more than just a first line (FL) therapy. METHODS: All patients who started FL for PAC at our institution (1997-2012) were retrospectively studied to identify patient's and treatment characteristics. Significant parameters in regard to second-line (SL) related survival were looked for as the basis for a prognostic model. This score was validated in a patient cohort from the CONKO-003 study. RESULTS: Two hundred eighty of 521 (53.7%) patients received SL therapy, median overall survival (OS) from the beginning of SL (OS2) was 5.1 months. Significant more SL patients had undergone surgery, a higher Karnofsky performance state (KPS) and a duration of FL longer than 4 months.Prognostic factors impacting OS2 were KPS, carbohydrate antigen 19-9 levels at start of SL and the duration of FL. These 3 factors establish a prognostic score-validated in CONKO-003-for SL patients with 3 subgroups: "good" (median OS2, 9.3 months), "intermediate" (median OS2, 7.1 months), "poor" prognosis (median OS2, 3.8 months; P < 0.001). CONCLUSIONS: Among patients with PAC, more than 50% receive SL therapy. Our prognostic model identifies 3 subgroups and can identify patients with a maximum benefit of SL therapy

A phase 2b study evaluating the efficacy and safety of subcutaneously administered tregalizumab in subjects with active Rheumatoid Arthritis (RA) despite treatment with Methotrexate (MTX)

Background/Purpose: In autoimmune diseases reduced numbers and functional impairment of regulatory T cells (Tregs) have been observed (1). Tregalizumab (BT-061) is a humanized, anti-CD4 mAb, inducing selective Treg activation in vitro. Previous trials suggested efficacy in RA at doses ≥25 mg subcutaneously (SC). In a population PK/PD analysis, down-modulation of CD4 expression was identified as a biomarker to monitor CD4 target engagement in humans. Methods: This two-part, Phase 2b randomized controlled trial (RCT) included subjects with active RA for ≥6 months despite MTX (≥15mg/wk), with ≥6/28 TJC, ≥6/28 SJC and elevated CRP or ESR. Subjects were randomized to receive 25 mg, 100 mg, 200 mg, or PBO once-weekly SC injection + MTX over 24 wks. Primary endpoint was ACR20 at wk 12. At wk 12 (end of Main part I), non-responders were re-randomized to active treatment or higher doses. Subjects responding at wk 24 (end of Main part II) could extend treatment for an additional 24 wks. A data safety monitoring board (DSMB) was established for safety evaluation throughout the study. Results: Of 321 subjects enrolled from Europe, USA, Canada, Russia and Mexico, 37 (11.5%) withdrew at ≤ wk 12. Demographics and baseline disease characteristics were well balanced across groups: mean SJC and TJC 16 and 24, respectively; CRP 11.7 mg/L, DAS (ESR) 6.58 and HAQ-DI 1.56. ACR20 responders at wk 12 (42.3%/47%/44.3% vs. 35.2% in 25 mg, 100 mg, 200 mg groups and PBO, respectively), ACR20 responders at wk 24 and secondary endpoints did not differ significantly between tregalizumab groups and PBO. However, dose dependent modulation of CD4 expression on T cells occurred rapidly with BT-061 treatment, as predicted from previous analyses. Through wk 12, TEAE (39.4% and 37.5%) and serious TEAEs rates (2.1% and 1.3%) were similar between BT-061 and PBO. For responder at wk 24, TEAEs (48.3% and 52.3%) were similar between BT-061 and PBO. Serious TEAEs were only reported in BT-061 treated subjects (2%). Three deaths occurred considered unrelated to treatment (car accident, acute coronary syndrome, death of unknown cause in a war area). There was no difference in infections between tregalizumab and PBO. One serious infection (peritonitis) occurred at wk 22 in the 25 mg dose group. Apart from acute coronary syndrome with fatal outcome, no further MACE events, Tuberculosis, opportunistic infections nor malignancies were reported. Conclusion: No tested doses of tregalizumab demonstrated significant efficacy improving signs and symptoms of active RA based on ACR20 responses at wk 12 and 24 despite dose dependent down-modulation of CD4 expression. Tregalizumab was generally well tolerated