What is the problem/issue being addressed?
Critical limb ischemia (CLI) is at the severe end of peripheral artery disease (PAD) spectrum when limb perfusion is reduced to tissue loss. Nutrient blood flow to the tissues and microcirculation exchange are seriously affected. As such CLI is associated with irreversible disability due to limb amputation, increased mortality rates and overall poor quality of life. Therapies targeting only the re-establishment of vascular patency (revascularization) and/or nascent collateral vessel formation by supporting vascularization have proven ineffective in a significant proportion of patients indicating the ischemic muscle tissue is not dispensable and therefore a “restoration of flow approach” is not independently sufficient to rescue the limb. Indeed, it is likely that myopathy and vasculopathy are interrelated components of a coordinated tissue response to CLI. Thus, current clinical interventions are largely ineffective and therapeutic angiogenesis-based trials have shown limited if any efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. The PACE placebo-controlled randomized clinical phase III trial is testing PLX-PAD placenta stromal cell therapy as novel therapeutic option for CLI, accompanied by biomarker and mechanistic studies to decipher the underlying clinical response profiles and mechanisms of action.
Why is it important for society?
PACE aimed for advancing clinical application of the “off-the-shelf” allogeneic placenta-derived stromal cell product (PLX-PAD) for critical limb ischemia (CLI) – a clinical indication with high unmet medical need – by performing a pivotal clinical trial integrated with mechanism-based research.
Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death (most studies report on 1-year amputation-free survival <60%; 10-year mortality 70%). CLI has a strong social impact and its incidence is rising worldwide, including in Europe. The prevalence of CLI in the population aged 60–90 years is estimated as 0.5–1.2% with male to female ratio around 3:1. Major risk factors for PAD include smoking, hyperlipidemia, hypertension, and, particularly for the development of CLI and diabetes. Diabetic patients are five-fold more likely to develop CLI than non-diabetic patients. The application of gene- and cell-based ATMP therapies to promote angiogenesis has been proposed as a novel concept to treat lower-limb CLI, particularly for patients with no options for revascularization. Proof of concept was demonstrated in animal models leading to clinical trials. The safety of these biologic therapies has been demonstrated, with no evidence of "off-target" angiogenesis, growth of occult tumors, or progression of diabetic retinopathy. Despite some failures particularly with single gene therapy, the results obtained from the recently published literature indicate a putative beneficial role of cell therapy, e.g. in ameliorating ischemic symptoms in CLI patients and improving their quality of life. However, there are several open questions regarding the optimal cell types, dosing, route of administration, combination, patient phenotype, and most critically, the proof of efficacy in large, well-controlled, and sufficiently powered clinical trials. In particular biomarker and mode-of-action (MoA) studies are of importance to better understand clinical trial outcomes. Thus, there is a need for i) well characterized off-the-shelf cell products manufactured in well-controlled, scalable, and robust GMP-procedures; and ii) more detailed analyses of patients prior to cell treatment to better define stratification parameters; and iii) an improved understanding on pharmacodynamics; and iv) to better understand the underlying MoA and to identify responders and non-responders to treatment or adverse effects as early as possible via state of the art biomarkers.Beyond the the primary goal of the study, to prove the usefulness of PLX cell therapy for combating severe CLI, we can learn many things from the project, such as i) heterogeneity of late stage CLI, ii) impact of intense gold-standard medical care (placebo arm) on course of severe disease, iii) comparability of cell products from different lots or even different sources (placenta donor), iv) in-depth profiling of PLX cell product that might be useful for other indications, v) standardized biomarker program applicable for different clinical studies.
