Periodic Reporting for period 2 - PACE (A multicenter phase IIb study using HLA-unmatched allogeneic placenta-derived stromal cells (PLX-PAD) for the treatment of severe critical limb ischemia accompanied by mechanistic studies)
Reporting period: 2018-07-01 to 2019-12-31
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. 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.
Why is it important for society?
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 (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. The major risk factors for PAD include smoking, hyperlipidemia, hypertension, and, particularly for development of CLI, diabetes. Diabetic patients are, at least, fivefold 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, the results obtained from the recent literature data have confirmed the putative beneficial role of cell therapy in ameliorating overall ischemic symptoms in patients with CLI and their quality of life. However, there are several open questions regarding the optimal cell types, dosing, route of administration, combination, patient phenotype, and critically, proof of efficacy in large controlled trials. Most importantly, recent clinical studies have several limitations.
Therefore, 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 define stratification parameters, iii) better understand pharmacodynamics and iv) describe mode-of-action to identify (non)response to treatment or adverse effects as early as possible via state of the art biomarkers.
What are the overall objectives?
To evaluate the efficacy, tolerability and safety of local intramuscular injections of HLA-unmatched allogeneic PLX-PAD cell products for the treatment of patients with CLI with minor tissue loss who are unsuitable for revascularization or had undergone several procedures in the past and are unlikely to benefit from additional interventions.
To present a model for the clinical development of a cell product using the new “Adaptive Pathways to Patients” (defined by the EMA).
To further characterize the molecular and functional signature of the PLX-PAD cell product(s).
To look beyond the traditional clinical trial endpoints of safety and efficacy, actively investigating the mechanisms of action of PLX-PAD therapy, exploring biomarkers in order to understand (non-)response in particular patients and to reveal the impact of the major risk factor, type 2 diabetes, on the response to therapy.
To disseminate our results for advancing clinical application of advanced therapy medicinal products (ATMPs) for indications with high-unmet medical need."
PACE clinical trial started successfully and at the end of 2019 more than 75% of the total patients were randomized into the clinical study. New in-depth analyses of the cell product characterization confirmed the robustness of PLX-PAD manufacturing. In addition, follow-up examinations of study patients started and increases our understanding on the mode-of-action of PLX-PAD.
Temporarily delays in patient recruitment have been overcome and we have seen a linear increase in recruitment for more than 12 months. Accordingly, the two related biomarker work packages faced minor delay, while the overall activities of the others are making good progresses.
In addition to the scientific progress, the overall awareness of the disease CLI and the PACE trial increased due to several dissemination activities performed by all partners. This includes for example a project website, press releases, project-specific flyers, and information material for the clinical sites as well as for the study subjects.
Altogether PACE can be a model for advancing the clinical development of ATMPs by an integrative approach based on a well-defined cell product, state-of-the-art clinical trial and accompanying biomarker and mechanistic in-patients studies.
A successful outcome for the PACE clinical trial can be rapidly translated into a new therapy for patients suffering from critical limb ischemia (CLI), a disease with high medical need and limited treatment. At the end, PACE will have significant impact on health services, research and patient management, and will generate guidelines for the development of other cell-based therapies according to the regulatory categorization into the “fast track” “Adaptive Pathways to Patient” program.