Single- and Multiple-Dose Pharmacokinetics and Pharmacodynamics of PN-943, a Gastrointestinal-Restricted Oral Peptide Antagonist of α4ß7, in Healthy Volunteers.

PN-943 is an orally stable, gastrointestinal-restricted peptide that binds specifically to α4ß7 integrin on leukocytes, blocking leukocyte trafficking to and activation in the gut, inhibiting colon inflammation and reducing signs and symptoms of active ulcerative colitis. Two pharmacokinetic/pharmacodynamic studies were conducted in healthy volunteers. Study 1 was a first-in-human study with 40 male subjects receiving PN-943, 100 to 1400 mg or placebo, as single doses and 57 male subjects receiving PN-943, 100 to 1000 mg or placebo, as multiple doses. Study 2 was a randomized, crossover study comparing multiple doses of 450-mg PN-943 twice daily as a liquid solution and as an immediate-release tablet in 10 subjects. No subjects discontinued due to treatment-emergent adverse events. Consistent with the gastrointestinal-restricted nature of the peptide, systemic exposure was minimal; there was an approximate dose-proportional increase in area under the plasma concentration-time curve. There was minimal accumulation with once-daily dosing and an absence of time-dependent changes in pharmacokinetics. Administration of PN-943 after a high-fat meal reduced peak plasma concentration and area under the plasma concentration-time curve. There was minimal (<0.1%) urinary excretion of intact drug, and there was a dose-related increase in fecal excretion of intact PN-943. Dose-dependent increases in blood receptor occupancy and reduction in blood receptor expression were observed, supporting target engagement. Twice-daily dosing resulted in sustained receptor occupancy with low plasma fluctuations (143%). PN-943 was generally well tolerated following single and multiple oral doses with low systemic exposure. Twice-daily dosing resulted in sustained pharmacokinetics and pharmacodynamics, supporting further investigation in efficacy studies.

Adjustment of the multi-biomarker disease activity score to account for age, sex and adiposity in patients with rheumatoid arthritis.

OBJECTIVE: To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA. METHODS: Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS). RESULTS: Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true. CONCLUSION: Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

Determination of the minimally important difference (MID) in multi-biomarker disease activity (MBDA) test scores: impact of diurnal and daily biomarker variation patterns on MBDA scores.

The Multi-Biomarker Disease Activity (MBDA) score is a validated rheumatoid arthritis (RA) disease activity measure based on 12 serum biomarkers. Here, we evaluate short-term biological variability of MBDA scores to determine the magnitude of change that might be considered clinically meaningful. Twenty-eight adult seropositive RA patients with clinically stable disease and no changes in RA medications for 4 weeks prior to study were enrolled. Nine serum samples were obtained over four consecutive days (non-fasting). MBDA score variation was assessed day-to-day (daily) and within 24 h (diurnal). The standard deviation (SD) of MBDA scores was calculated by a linear mixed model including random effects for patient, day, and time of day. The minimally important difference (MID) was calculated as [Formula: see text]. A subgroup analysis was performed for patients with active RA (moderate or high MBDA score). The SD of MBDA score change in the full cohort was 4.7 in a combined daily-diurnal variation analysis, which corresponds with an MID of 11. The SD of MBDA score change in the subset of patients with active RA (moderate/high MBDA scores) was 3.6. This corresponds with an MID of 8 units in patients with active RA for whom clinicians are most likely to need guidance with respect to therapeutic decisions. Changes in MBDA score ≥ 8 represent a change in RA disease activity that clinicians can use as a benchmark for therapeutic drug efficacy and can be incorporated into a treat-to-target strategy.

The multi-biomarker disease activity score tracks response to rituximab treatment in rheumatoid arthritis patients: a post hoc analysis of three cohort studies.

BACKGROUND: A multi-biomarker disease activity (MBDA) score has been validated as an objective measure of disease activity in rheumatoid arthritis (RA) and shown to track response to treatment with several disease-modifying anti-rheumatic drugs (DMARDs). The objective of this study was to evaluate the ability of the MBDA score to track response to treatment with rituximab. METHODS: Data were used from 57 RA patients from three cohorts treated with rituximab 1000 mg and methylprednisolone 100 mg at days 1 and 15. The MBDA score was assessed in serum samples obtained at baseline and 6 months. Spearman's rank correlation coefficients were calculated for baseline values, 6-month values, and change from baseline to 6 months (∆), between MBDA score and the following measures: disease activity score assessing 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) or high-sensitivity C-reactive protein (hsCRP), ESR, (hs)CRP, swollen and tender joint counts assessing 28 joints (SJC28, TJC28), patient visual analogue scale for general health (VAS-GH), health assessment questionnaire (HAQ), and radiographic progression over 12 months using Sharp/van der Heijde score (SHS), as well as six bone turnover markers. Additionally, multivariable linear regression analyses were performed using these measures as dependent variable and the MBDA score as independent variable, with adjustment for relevant confounders. The association between ∆MBDA score and European League Against Rheumatism (EULAR) response at 6 months was assessed with adjustment for relevant confounders. RESULTS: At baseline, the median MBDA score and DAS28-ESR were 54.0 (IQR 44.3-70.0) and 6.3 (IQR 5.4-7.1), respectively. MBDA scores correlated significantly with DAS28-ESR, DAS28-hsCRP, ESR and (hs)CRP at baseline and 6 months. ∆MBDA score correlated significantly with changes in these measures. ∆MBDA score was associated with EULAR good or moderate response (adjusted OR = 0.89, 95% CI = 0.81-0.98, p = 0.02). Neither baseline MBDA score nor ΔMBDA score correlated statistically significantly with ∆SHS (n = 11) or change in bone turnover markers (n = 23), although ∆SHS ≥ 5 was observed in 5 (56%) of nine patients with high MBDA scores. CONCLUSIONS: We have shown, for the first time, that the MBDA score tracked disease activity in RA patients treated with rituximab and that change in MBDA score reflected the degree of treatment response.