Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure.

Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell-based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF with reduced ejection fraction studies, the joint frailty model is utilized to reflect characteristics of the high-risk patient population with important unmet therapeutic needs. In some cases, use of the joint frailty model may substantially reduce sample size requirements. In addition, using an end point that is acceptable to the Food and Drug Administration and the European Medicines Agency, such as recurrent nonfatal HF-related major adverse cardiac events, enables generation of clinically relevant pharmacoeconomic data while providing comprehensive views of the patient's overall cardiovascular disease burden. The major goal of this review is to provide lessons learned from the ongoing DREAM-HF trial that relate to biologic plausibility and flexible clinical trial design and are potentially applicable to other development programs of innovative therapies for patients with advanced cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02032004.

A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure.

RATIONALE: Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). OBJECTIVE: To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. METHODS AND RESULTS: We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan-Meier statistics >3 years (P=0.025 for 150 million MPC group versus control). CONCLUSIONS: Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.

Prospective randomized controlled trial of the safety and feasibility of a novel mesenchymal precursor cell therapy in hypoplastic left heart syndrome.

Objective: To assess the safety and feasibility of low-dose, novel, allogenic mesenchymal precursor cell (MPC) therapy as an adjunct to left ventricular (LV) recruitment for patients with hypoplastic left heart syndrome (HLHS) and borderline left ventricles. MPC injections into the hypoplastic left ventricle may stimulate neovascularization and beneficial LV remodeling and may improve the likelihood of achieving biventricular (BiV) or 1.5 ventricle (1.5V) circulation. Methods: Children <5 years with prior single ventricle palliation undergoing LV recruitment surgery at a single center were randomized to MPC injections into the LV endocardium/papillary muscles (MPCs) or standard-of-care (controls) and followed for 24 months. The primary endpoint was safety, including (serious) adverse events (S/AEs), and panel reactive antibodies (PRAs). Secondary endpoints included BiV/1.5V conversion and LV size and function. Results: Nineteen subjects were enrolled, including 9 MPC recipients and 10 controls. Fourteen patients (74%) had >1 AE, and 2 patients had SAEs, both deemed unrelated to the trial product. AE severity and frequency were similar in the 2 groups. Baseline PRA levels were high, with no difference between the groups at 12 months. The overall probability of BiV/1.5V conversion was 0.16 (95% confidence interval [CI], 0.05 to 0.41) at 12 months and 0.52 (95% CI, 0.31 to 0.77) at 24 months. For patients with imaging data at both time points, increases in LV volumes from baseline to 12 months were larger in the MPC group by 3-dimensional echocardiography and cardiac magnetic resonance imaging. For children who successfully underwent BiV conversion (n = 12), full BiV conversion was achieved at 24 months in 5 of 5 (100%) MPC-treated children compared with 4 of 7 (57%) controls. Conclusions: MPC injections were considered safe and feasible in HLHS patients. More than 50% of subjects underwent BiV/1.5V conversion within 2 years. Larger trials are needed to investigate the therapeutic potential of MPCs in this population.

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

BACKGROUND: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF. METHODS: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity. RESULTS: The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L). CONCLUSIONS: The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.

Remestemcel-L Therapy for COVID-19-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a serious postinfectious immune dysregulation associated with coronavirus disease 2019 that may present with severe and life-threatening cardiovascular dysfunction, hemodynamic instability, shock, and multisystem organ failure. Optimal treatment is unknown. Current standard of care consists of nonspecific anti-inflammatory and antithrombotic therapies. Interventions that target MIS-C's distinctive clinical features and immunophenotype are indicated. Remestemcel-L, an investigational mesenchymal stromal cell therapy, is a promising candidate for treatment of MIS-C because of its beneficial anti-inflammatory, immunomodulatory, endothelial function and vascular stabilizing effects, which align well with the pathophysiology of MIS-C. Here, we present the first two patients with life-threatening MIS-C ever treated with remestemcel-L under an expanded access program. Both were previously healthy children without any indication of previous coronavirus disease 2019 infection or exposure. They presented with severe clinical illness including myocardial dysfunction, hemodynamic instability, hypotension, acute kidney injury, and shock. At the time of hospital admission, both had negative polymerase chain reaction (PCR) test results and positive serology results for severe acute respiratory syndrome coronavirus 2. Both children received standard of care MIS-C treatment. Although the patients showed some clinical improvement, left ventricular ejection fraction remained reduced and inflammatory biomarkers remained significantly elevated. When treated with two intravenous doses of remestemcel-L separated by 48 hours, rapid normalization of left ventricular ejection fraction, notable reductions in biomarkers of systemic and cardiac inflammation, and improved clinical status occurred. Neither child experienced adverse effects associated with remestemcel-L administration. This treatment appears promising as a novel immunomodulatory cellular therapy for children with clinically significant cardiovascular manifestations of MIS-C.

Eicosapentaenoic Acid as a Potential Therapeutic Approach to Reduce Cardiovascular Risk in Patients with End-Stage Renal Disease on Hemodialysis: A Review.

BACKGROUND: Patients with end-stage renal disease on hemodialysis have excess cardiovascular disease (CVD) burden with substantially increased CV event rates compared with the general population. SUMMARY: Traditional interventions that, according to standard clinical guidelines, reduce CV risk such as antihypertensive therapy, diet, exercise, and statins are not similarly effective in the hemodialysis population. This raises the question of whether additional risk factors, such as enhanced inflammation and oxidative stress, may drive the increased CVD burden in hemodialysis patients. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into the atherosclerotic plaque as well as membrane phospholipid bilayers and produces beneficial effects on inflammatory and oxidative mechanisms involved in atherosclerotic plaque formation and progression. EPA levels and the ratio of EPA to the omega-6 polyunsaturated fatty acid arachidonic acid (AA) are reduced in hemodialysis patients. Serum EPA levels have been inversely correlated with proinflammatory cytokines, and the EPA/AA ratio has been inversely associated with CV events in hemodialysis cohorts. Three recent studies involving over 800 hemodialysis patients and follow-up of 2-3 years suggest that EPA therapy may improve clinical outcomes in this patient population as evidenced by significant reductions in cardiovascular mortality, all-cause mortality, and/or CV events. KEY MESSAGES: Further studies with high-purity EPA are warranted in patients on hemodialysis, especially given the fact that other interventions including antihypertensives, diet, exercise, and statins have not provided meaningful benefit.

Optimizing Cholesterol Treatment in Patients With Muscle Complaints.

Statins are highly effective for preventing cardiovascular events by reducing low-density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms.

Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.

Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects are at least additive to those of statins when given as adjunctive therapy. In this review, we present data supporting the biologic plausibility of EPA as an anti-atherosclerotic agent with potential clinical benefit for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT is an ongoing, randomized, controlled study evaluating whether the high-purity ethyl ester of EPA (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk.