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Novel Stromal Cell Therapy for Diabetic Kidney Disease

Periodic Reporting for period 4 - NEPHSTROM (Novel Stromal Cell Therapy for Diabetic Kidney Disease)

Reporting period: 2019-05-01 to 2020-10-31

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 in Ireland, the U.K. and Italy will evaluate the clinical safety and efficacy of GMP-compliant ORBCEL-M in a 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.
In the period covered by this report, NEPHSTROM has continued to make progress towards achieving its objectives. We have completed our extensive programme of pre-clinical experiments to investigate the biodistribution, persistence, and clinically-relevant anti-inflammatory effects of ORBCEL-M in mouse models of DKD, in addition to investigating the mechanism of action of ORBCEL-M using an in vitro cell line and in our DKD mouse model. Our current results demonstrate one possible mechanism-of-action of ORBCEL in diabetic nephropathy animals is by regulating the inflammatory milieu and restoration of podocyte function in the glomeruli of diseased animals. In the mechanism of action task we also examined the immunological mechanisms determining the fate of infused MSC and the immunomodulatory response associated with it, as part of our ongoing task investigating stromal cell ablation and cell engraftment of ORBCEL MSC.

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. Our cell production partners worked together closely to standardise and validate production procedures to develop a single GMP-compliant manufacturing system that is fully approved by the regulatory authorities. In the period covered by this report, cell production of the range of doses required for the clinical trial was fully completed. We have demonstrated the clinical feasibility of our innovative approach to cell production.

The partners involved in the clinical trial have worked together to fulfil the requirements for Ethical and Regulatory approvals of the study and to set up the organization of the trial and associated bio-sampling/bio-banking procedures in each participating centre. The NEPHSTROM Clinical Trial Dossier has been evaluated and approved by the VHP Coordinator and by the National Competent Authorities and Research Ethics Committee of the centres participating in this multicentre, multinational clinical study and any required amendments to the Clinical Trial Dossier to facilitate recruitment have been approved. The first patient infusion of NEPHSTROM ORBCEL-M or placebo took place in the ASST-PG23 clinical centre in June 2018. Since then the clinical centres actively screened patients in their clinics in order to identify potential candidates for the NEPHSTROM trial. To date and after passing detailed screening 11 patients have proceeded to cell or placebo infusion with NEPHSTROM ORBCEL-M or placebo. No early and long-term safety issues related to the single cell product/placebo infusion have been reported to date. More patients are scheduled to receive cell or placebo infusion in the coming months.
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. The project has already made significant progress towards the achievement of its expected impacts and, notwithstanding the difficulties resulting from the Covid-19 pandemic, and the recruitment and treatment of patients is currently ongoing.

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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