Periodic Reporting for period 5 - NEPHSTROM (Novel Stromal Cell Therapy for Diabetic Kidney Disease)
Periodo di rendicontazione: 2020-11-01 al 2021-10-31
Diabetes is a global epidemic. The disease and 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 project was designed to test and validate 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 evaluated the clinical safety and efficacy of GMP-compliant ORBCEL-M in a Phase 1b/2a clinical trial in patients suffering from DKD. While safety was the primary endpoint, we were 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 carried out within the NEPHSTROM project was 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 evaluated 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.
The NEPHSTROM project was designed to test and validate 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 evaluated the clinical safety and efficacy of GMP-compliant ORBCEL-M in a Phase 1b/2a clinical trial in patients suffering from DKD. While safety was the primary endpoint, we were 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 carried out within the NEPHSTROM project was 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 evaluated 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.
The NEPHSTROM project addressed and largely achieved an ambitious range of important objectives.
We completed an 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 results demonstrated 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.
NEPHSTROM developed a pan-European cell-production infrastructure. 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. The 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 clinical trial at the heart of NEPHSTROM had to address a number of significant challenges, most notably the impact of Covid-19. Notwithstanding this, while we have been unable to deliver the trial as originally planned, we have made very significant progress towards achieving this objective. Fourteen out of sixteen DKD patients who received the scheduled lowest dose of NEPHSTROM ORBCEL-M (80 x 106 cells) or placebo (first cohort of NEPHSTROM trial) we successfully followed the end of the planned follow-up (18 months, 2 dropped out at month 15 follow-up due to SAE). Our findings indicate that, in the treated subjects belonging to the first cohort of the NEPHSTROM trial, the tolerability and safety profile of the IMP/placebo infusion (primary end-point) were acceptable and sustained in the months thereafter up to the end of the 18-month follow-up. The project team is committed to completing the trial, using the partners’ own resources and with assistance from ORB.
We completed an 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 results demonstrated 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.
NEPHSTROM developed a pan-European cell-production infrastructure. 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. The 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 clinical trial at the heart of NEPHSTROM had to address a number of significant challenges, most notably the impact of Covid-19. Notwithstanding this, while we have been unable to deliver the trial as originally planned, we have made very significant progress towards achieving this objective. Fourteen out of sixteen DKD patients who received the scheduled lowest dose of NEPHSTROM ORBCEL-M (80 x 106 cells) or placebo (first cohort of NEPHSTROM trial) we successfully followed the end of the planned follow-up (18 months, 2 dropped out at month 15 follow-up due to SAE). Our findings indicate that, in the treated subjects belonging to the first cohort of the NEPHSTROM trial, the tolerability and safety profile of the IMP/placebo infusion (primary end-point) were acceptable and sustained in the months thereafter up to the end of the 18-month follow-up. The project team is committed to completing the trial, using the partners’ own resources and with assistance from ORB.
The principal impact of NEPHSTROM has been the development of a novel therapy for a common non-communicable disease, which prevents or delays 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.
New therapeutic strategies, with the highest potential to generate advances in clinical practice for chronic diseases, ready for further development
NEPHSTROM validated a new therapeutic strategy for DKD. By validating the safety of ORBCEL-M in humans, NEPHSTROM laid the groundwork for the eventual clinical usefulness of the treatment. The preparation carried out for the NEPHSTROM trial, including the completion and submission of regulatory documentation, the selection of GMP-compliant manufacturing reagents and processes, and the validation of the next-generation, closed-automated manufacturing system required to isolate and produce the ORBCEL-M therapy at scale are all key infrastructural elements in ensuring the impact of NEPHSTROM, and in positioning ORBCEL-M for further development and clinical adoption. In addition, the network of European cell therapy manufacturing centres that has been developed by NEPHSTROM will play a key role in addressing the challenge of cell production for future trials and eventually for market.
Improving Innovation Capacity
NEPHSTROM’s innovation focus is firmly on a better therapy for DKD through regenerative medicine – the use of cell therapies to cure previously intractable diseases. The results of the project will have extensive benefits for the partners involved and also for the broader European research community. Partners involved in cell production have worked together to develop a cell-production network, using a combined, closed, automated manufacturing process, and an innovative approach to production.
NEPHSTROM’s impact has also been significant for the research institutions involved in the project. The funding secured has allowed partners to develop their research on the mechanism of action and the immunological properties of MSCs and has given researchers the opportunity to gain proficiency with new techniques.
New therapeutic strategies, with the highest potential to generate advances in clinical practice for chronic diseases, ready for further development
NEPHSTROM validated a new therapeutic strategy for DKD. By validating the safety of ORBCEL-M in humans, NEPHSTROM laid the groundwork for the eventual clinical usefulness of the treatment. The preparation carried out for the NEPHSTROM trial, including the completion and submission of regulatory documentation, the selection of GMP-compliant manufacturing reagents and processes, and the validation of the next-generation, closed-automated manufacturing system required to isolate and produce the ORBCEL-M therapy at scale are all key infrastructural elements in ensuring the impact of NEPHSTROM, and in positioning ORBCEL-M for further development and clinical adoption. In addition, the network of European cell therapy manufacturing centres that has been developed by NEPHSTROM will play a key role in addressing the challenge of cell production for future trials and eventually for market.
Improving Innovation Capacity
NEPHSTROM’s innovation focus is firmly on a better therapy for DKD through regenerative medicine – the use of cell therapies to cure previously intractable diseases. The results of the project will have extensive benefits for the partners involved and also for the broader European research community. Partners involved in cell production have worked together to develop a cell-production network, using a combined, closed, automated manufacturing process, and an innovative approach to production.
NEPHSTROM’s impact has also been significant for the research institutions involved in the project. The funding secured has allowed partners to develop their research on the mechanism of action and the immunological properties of MSCs and has given researchers the opportunity to gain proficiency with new techniques.