Effectiveness and Safety of Adalimumab Biosimilar SB5 in Inflammatory Bowel Disease: Outcomes in Originator to SB5 Switch, Double Biosimilar Switch and Bio-Naïve SB5 Observational Cohorts.

BACKGROUND AND AIMS: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. METHODS: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. RESULTS: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6-15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2-12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. CONCLUSION: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up.

Association of trough vedolizumab levels with clinical, biological and endoscopic outcomes during maintenance therapy in inflammatory bowel disease.

OBJECTIVE: To establish the relationship between trough vedolizumab levels and outcomes during maintenance therapy. DESIGN: Cross-sectional service evaluation was performed on patients with inflammatory bowel disease (IBD) receiving maintenance vedolizumab therapy (minimum of 12 weeks following induction). Prior to infusion, data on clinical activity (Harvey-Bradshaw Index or partial Mayo score), trough C-reactive protein (CRP)/vedolizumab levels and faecal calprotectin were collected. Endoscopic data (±8 weeks from vedolizumab level testing) were obtained by review of medical records. Vedolizumab levels were processed using the Immundiagnostik monitor ELISA. SETTING: The Edinburgh IBD Unit, Western General Hospital (tertiary IBD referral centre). PATIENTS: Seventy-three patients (30 ulcerative colitis and 43 Crohn's disease) were identified who fulfilled inclusion criteria and had vedolizumab levels matched with clinical activity scores, CRP and faecal calprotectin. Of these, 40 patients also had matched endoscopic data. MAIN OUTCOME MEASURES: The association of trough vedolizumab levels with clinical remission (Harvey-Bradshaw Index <5 or partial Mayo <2), biologic remission (faecal calprotectin <250 µg/g+CRP <5 mg/L) and endoscopic remission (Mayo score 0/no inflammation and ulceration on colonoscopy). RESULTS: The median trough vedolizumab levels were similar between patients in and not in clinical remission (10.6 vs 9.9 µg/mL, p=0.54); biologic remission (10.6 vs 9.8 µg/mL, p=0.35) and endoscopic remission (8.1 vs 10.2 µg/mL, p=0.21). Quartile analysis revealed no significant increase in the proportion of patients in clinical remission, biologic remission or endoscopic remission with increasing trough vedolizumab levels (p<0.05). CONCLUSIONS: In this cohort, trough vedolizumab levels were not associated with clinical, biological or endoscopic outcomes during maintenance therapy.

Implementation of CT-P13 via a Managed Switch Programme in Crohn's Disease: 12-Month Real-World Outcomes.

BACKGROUND: Switching from Remicade to CT-P13 allows for significant cost savings and has been shown to be non-inferior to continued therapy with Remicade for the treatment of Crohn's disease. AIM: The aim of this work was to prospectively evaluate clinical outcomes in a cohort of patients with Crohn's disease switching from Remicade to CT-P13. METHODS: A prospective service evaluation was performed. The Harvey-Bradshaw index, CRP, faecal calprotectin and serum for infliximab/antibody levels were collected prior to patients' final Remicade infusion and at 6 and 12 months after switching to CT-P13 as part of routine clinical care. All adverse events during follow-up were also recorded. RESULTS: One hundred and ten patients on Remicade switched to CT-P13. No significant difference was observed between the Harvey-Bradshaw Index (p = 0.07), CRP (p = 0.13), faecal calprotectin (p = 0.25) or trough infliximab levels (p = 0.47) comparing before and at 6 and 12 months after the switch to CT-P13. Seven patients developed new infliximab antibodies after switching from Remicade to CT-P13. The majority of patients remained on CT-P13 at 12 months (84.5%) and the rate of adverse events and serious adverse events was 53.8 and 13.5 per 100 patient-years of follow-up, respectively. Switching to CT-P13 resulted in a cost saving of approximately 46.4%. CONCLUSION: The transition to CT-P13 from Remicade for the treatment of Crohn's disease is safe and has no negative effect on clinical outcomes at 12 months.

Higher Adalimumab Drug Levels During Maintenance Therapy for Crohn's Disease Are Associated With Biologic Remission.

BACKGROUND: Adalimumab is an established treatment for Crohn's disease. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut inflammation. We therefore aimed to characterize the relationship between adalimumab levels and biologic remission during maintenance therapy. METHODS: A single-center prospective cross-sectional study was undertaken on Crohn's disease patients who had received adalimumab therapy for a minimum of 12 weeks after induction. Data on clinical activity (Harvey-Bradshaw Index), C-reactive protein (CRP), adalimumab drug and antibody levels, and fecal calprotectin were collected. Biologic remission was defined as a CRP <5 mg/L and fecal calprotectin <250 µg/g. Adalimumab drug and antibody levels were processed using the Immundiagnostik monitor enzyme-linked immunosorbent assay. RESULTS: One hundred fifty-two patients had drug and antibody samples matched with CRP and fecal calprotectin. Patients in biologic remission had significantly higher adalimumab levels compared with others (12.0 µg/mL vs 8.0 µg/mL, P < 0.0001). Receiver operating characteristic curve analysis demonstrated an optimal adalimumab level of >8.5 µg/mL (sensitivity, 82.2%; specificity, 55.7%; likelihood ratio, 1.9) for predicting biologic remission. Multivariable logistic regression revealed that adalimumab levels >8.5 µg/mL were independently associated with biologic remission (odds ratio, 5.27; 95% confidence interval, 2.43-11.44; P < 0.0001). CONCLUSIONS: Higher adalimumab levels are associated with biologic remission. An optimal level of >8.5 µg/mL was identified.

Climate Process Team on Internal Wave-Driven Ocean Mixing.

Diapycnal mixing plays a primary role in the thermodynamic balance of the ocean and, consequently, in oceanic heat and carbon uptake and storage. Though observed mixing rates are on average consistent with values required by inverse models, recent attention has focused on the dramatic spatial variability, spanning several orders of magnitude, of mixing rates in both the upper and deep ocean. Away from ocean boundaries, the spatio-temporal patterns of mixing are largely driven by the geography of generation, propagation and dissipation of internal waves, which supply much of the power for turbulent mixing. Over the last five years and under the auspices of US CLIVAR, a NSF- and NOAA-supported Climate Process Team has been engaged in developing, implementing and testing dynamics-based parameterizations for internal-wave driven turbulent mixing in global ocean models. The work has primarily focused on turbulence 1) near sites of internal tide generation, 2) in the upper ocean related to wind-generated near inertial motions, 3) due to internal lee waves generated by low-frequency mesoscale flows over topography, and 4) at ocean margins. Here we review recent progress, describe the tools developed, and discuss future directions.

Adaptive filtering of vibrissa input in motor cortex of rat.

We studied the transformation of sensory input as it progresses from vibrissa primary sensor (S1) to motor (M1) cortex. Single-unit activity was obtained from alert adult rats that did not to whisk upon application of punctate, rhythmic stimulation of individual vibrissae. The spike response of units in S1 cortex largely reproduced the shape of the stimulus. In contrast, the spiking output of units in M1 cortex were modulated solely as a sinusoid at the repetition rate of the stimulus for frequencies between 5 and 15 Hz; this range corresponds to that of natural whisking. Thus, the S1 to M1 transformation extracts the fundamental frequency from a spectrally rich stimulus. We discuss our results in terms of a band-pass filter with a center frequency that adapts to the change in stimulation rate.