Periodic Reporting for period 3 - 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: 2020-01-01 to 2021-06-30
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 development of CLI, 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.
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 clinical trial integrated with mechanism-based research.
The PACE clinical trial has been terminated after 213 of 246 patients were recruited, because of recommendation by the DSMB based on their interim analysis revealing that the achievement of the primary endpoint was not likely. On 07 March 2021 Data Base Lock (DBL) was performed . Clinical data analysis and is currently ongoing, to be completed by the end of 2021. Most importantly, we want to understand whether secondary endpoints and/or patient subgroup analyses reveal a treatment effect for PLX-PAD. This is critical for the decision how to proceed with this indication and what can we learn for future trials in CLI as no new drug was approved during the last decade. In addition, in-depth analyses of the cell product characterization have confirmed the robustness of PLX-PAD manufacturing for clinical use. Follow-up clinical and biomarker examinations of the study patients, such as blood serum/plasma cytokine biomarker analysis, peripheral circulating blood cell transcriptome analysis with next-generation sequencing (NGS / RNAseq), and PLX-directed alloimmune responsiveness studies (cellular and humoral response) of patients are currently ongoing, to increase our understanding on the mode-of-action of PLX-PAD in vivo. This is further supported by in vitro modeling on the putative MoA of PLX-PAD in preclinical model systems, such as (multi)organ-on-chip model. All preclinical and clinical data are currently combined in a database/repository to be also available after project completion. Altogether PACE can be considered 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. Importantly, for public benefit and maximum transparency we are now preparing the publication of the obtained study results with adjunct clinical response biomarker analysis and cell product characterization.
Moreover, it demonstrates that an off-the-shelf manufacturing of an allogenic cell product is feasible, robust, and safe with high lot-to-lot and donor-to-donor consistency.