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NEPHSTROM Report Summary

Project ID: 634086
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - NEPHSTROM (Novel Stromal Cell Therapy for Diabetic Kidney Disease)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

Diabetes is a global epidemic. The disease and (especially) its complications and co-morbidities kill one European every minute. More than 10% of these deaths are directly linked to diabetic kidney disease (DKD). DKD and End-Stage Renal Disease consume between 10% and 15% of global healthcare spending. Outcomes for patients with diabetes, hypertension and cardio- vascular disease are much less positive, if they also have DKD. There is no cure for DKD. Even with optimal pharmacological care, patients typically progress to End-Stage Renal Disease, dialysis, transplant (where feasible) and death.

The NEPHSTROM team is testing and validating a novel stem cell therapy (ORBCEL-M, from Orbsen Therapeutics) For DKD. This therapy has already been shown to improve four key indicators of DKD (Glomerular Filtration Rate, or GFR; proteinurea; glomerulosclerosis; and inflammation) in mouse models. This excellent evidence, from the FP7 REDDSTAR project, has enabled us to progress to clinical and regulatory submissions for a first-in-man trial of this novel cell therapy ORBCEL-M for DKD.

As part of NEPHSTROM, clinicians at BHSCT (Belfast), UHBFT (Birmingham), NUIG (Galway) and IRFMN (Bergamo) will evaluate the clinical safety and efficacy of GMP-compliant ORBCEL-M in a four-site Phase 1b/2a clinical trial in patients suffering from DKD. While safety is the primary endpoint, we are also looking for initial indications of efficacy, to encourage further trials.

NEPHSTROM is also addressing the challenge of scaling cell production to meet increased clinical demand, as soon as clear positive clinical results are published. This is a key challenge for any cell therapy, including ORBCEL-M. In NEPHSTROM, we are establishing and validating a network of cell production centres, using common cell stock, across Europe. This is a key enabler for any later-stage clinical trial, and for clinical use.

The cell production and clinical work is supplemented and supported by a programme of investigation into the efficacy, mechanism of action, immune response and bio-distribution of ORBCEL-M in animal models. In addition, the project will evaluate the economic benefit of this novel cell therapy relative to current treatment scenarios. The information gained here will be critical for planning for future later-stage clinical trials.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first eighteen months of the project, NEPHSTROM has made excellent progress towards achieving its objectives. We have carried out extensive pre-clinical experiments to investigate the biodistribution, persistence, and clinically-relevant anti-inflammatory effects of ORBCEL-M in mouse models of DKD. Using novel CryoViz® technology, we have investigated the distribution of injected ORBCELL-M cells, and have demonstrated their persistence in in tissue for up to four days after injection. We have also carried out experiments to evaluate the anti-inflammatory effects of ORBCEL-M in the mouse model. In addition, we have investigated the mechanism of action of ORBCEL-M, using an in vitro cell line.

The development of a pan-European cell-production infrastructure is vitally important to NEPHSTROM, both as an overall objective of the project, and an essential element in carrying out the clinical trial. Over the first eighteen months of the project, our cell production partners have worked together closely to standardise and validate production procedures to develop a GMP production procedures. A number of innovative technologies for cell isolation and culture have been integrated into a single GMP-compliant manufacturing system. As a result of this progress means, we are is now prepared to begin cell production fot the NEPHSTROM clinical trial.

Preparations for the clinical trial have been the third major focus of the project in the first eighteen months. In preparation for a submission to European regulators for the approval of the NEPHSTROM trial, complex and detailed documentation, including an Investigational Medicinal Product Dossier (IPMD) and Investigative Brochure (IB) has been prepared and submitted.

As a result of this work, the essential groundwork for the NEPHSTROM trial has been laid. The cell production infrastructure needed has been established and engagement with the regulators has been initiated. At the same time, important progress has been made in the project’s pre-clinical work, enabling a deeper understanding of the work done by ORBCEL-M cells in helping to reverse the damage caused by DKD.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The principal impact of NEPHSTROM will be the development of a novel therapy for a common non-communicable disease, which will prevent or delay organ failure by enhancing organ repair and regeneration. The limitations of existing therapies will be overcome by an approach requiring simple intravenous delivery of an allogeneic cell therapy product. Better therapeutic outcomes will be secured by reducing the requirement for kidney transplant, dialysis and long-term polypharmacy. Low-trauma, lower-cost therapies will reduce the burden of disease for patients and healthcare systems. A pan-European production network, equipped to meet the demands of clinical cell production, and using a GMP-compliant, closed, cell-production system will support the needs of the project and provide a key infrastructure to support the clinical mainstreaming of cell therapy.

The completion of the NEPHSTROM clinical trial will be essential to the successful achievement of the project’s planned impacts. However, in the first reporting period covered by this report, the project has already made progress towards the achievement of its expected impacts.

The project has been active in disseminating its work through a variety of channels. These include online dissemination, social media, and interactions with patient groups and pharmaceutical companies, as well as through academic papers.

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