Abstract
BackgroundWe previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels.MethodsTime course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels.ResultsIn COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups.ConclusionIn an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases.Trial registration: Clinicaltrials.gov NCT00683722.
Highlights
We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic Mesenchymal stromal cell (MSC) in Chronic obstructive pulmonary disease (COPD)
While systemic MSC administration has proven safe and well-tolerated in clinical investigations, there has been no clear evidence of efficacy to date in a spectrum of lung disease patients studied including those with COPD [5,6,7]
Changes over the 2-year study period in FEV1, FVC, and 6 minute walk distance (6MWD), and in circulating C-reactive protein (CRP) levels in subjects with baseline CRP ≥ 4 mg/L in those receiving remestemcel-L vs. placebo are shown in Figs. 1 and 3, respectively
Summary
We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While systemic MSC administration has proven safe and well-tolerated in clinical investigations, there has been no clear evidence of efficacy to date in a spectrum of lung disease patients studied including those with COPD [5,6,7]. We previously reported results of a placebo-controlled trial [NCT00683722] of systemic infusions of bone marrowderived allogeneic MSCs in patients with moderate to severe COPD that included 62 patients with moderate or severe COPD (GOLD spirometry stage 2 or stage 3) randomized at six participating sites to double-blinded intravenous infusions of remestemcel-L, formerly ProchymalTM, (108 cells/ infusion) or vehicle control [8]. One novel observation was that, in patients with elevated baseline CRP levels at study entry, a statistically significant CRP decrease was observed over the initial months of the study in patients receiving remestemcel-L compared to placebo, and a non-significant trend persisted over the two year observation period
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