Periodic Reporting for period 1 - AMELIE (Anchored Muscle cELls for IncontinencE)
Période du rapport: 2020-09-01 au 2022-02-28
Faecal incontinence (FI) is a common condition affecting ~9% European adults (~67 million people). Whilst not life threatening, it is classified as a disease by the World Health Organization (WHO) that seriously impairs daily living and productivity of affected individuals and their families, resulting in a substantial burden on European health services.
FI is closely associated with age and is more common in residential and nursing homes affecting one in three people living in residential care and two in three nursing home residents. There is a particular therapeutic unmet need for patients with severe symptoms of FI, who are either unsuitable for, or do not wish to undergo, currently available surgical options, but who may benefit from a regenerative medical approach. There is scientific rationale and evidence that women with FI arising from obstetric anal sphincter injury, the clinical symptoms of which may appear some decades after childbirth, may most benefit from this approach and are therefore the primary target patient group in the AMELIE project. FI in postpartum women arising from obstetric sphincter injury has a reported incidence of 5.5%. In 2017, approximately 5.06 million babies were born in the European Union, suggesting ~222,640 women per annum in the EU could benefit from a regenerative medical approach.
To date, cell therapy studies using anchorage dependent cells, such as autologous skeletal muscle derived cells, are constrained by sub-optimal manufacturing techniques originally established for other purposes, prior to the advent of cell therapy. The process of detaching anchorage-dependent skeletal muscle-derived cells (SMDC) during bioprocessing and their subsequent delivery into patients as a cell suspension poses significant risks of damaging the cells through the process of anoikis (an apoptosis pathway triggered in anchorage-dependent cells when they detach from their substratum), resulting in reduced potency of the product and inconsistent response to the therapy.
To circumvent these therapeutic failings, the AMELIE consortium is developing a radical, innovative translational approach to manufacture and deliver anchorage-dependent cells into the body to establish more effective regenerative medicine therapies for FI and other clinical indications. To achieve this, we have developed a novel tissue engineered product (combined advanced therapy medicinal product) that comprises attaching the anchorage dependent cells to an implantable biodegradable, clinically qualified microcarrier. This product provides an effective substrate for cell attachment and expansion during in vitro manufacture and a system for minimally invasive, targeted in vivo delivery of cells in their natural anchored state. This will increase in vivo survival of the active component of the cell therapy after implantation, increasing the likelihood of anal sphincter regeneration.
To develop the new implantable microcarrier technology for use in regenerative medicine, the AMELIE project has the following objectives:
1. Establish new robust processes for the scalable manufacture, characterization, transportation and delivery of the implantable cell-microcarrier combination investigational product.
2. Demonstrate safety of the implantable cell-microcarrier combination investigational product using non-clinical testing to comply with national regulatory requirements and create an investigational medicinal product dossier that will enable evaluation of the technology across Europe.
3. Conduct a pan-European multi-centre, randomised, double-blind (phase I/IIb) trial to determine whether the investigation product (implantable cell-microcarrier combination) leads to a minimum clinically-relevant reduction in frequency of total FI episodes compared to control procedure.
4. Involve national and regional FI societies, patient support networks and the public throughout the project to establish suitable two-way channels for PPI activity and dissemination of project developments to patients, general public and scientific community.
5. Develop a business plan and future commercialisation strategy to enable patient access to the implantable cell-microcarrier combination across Europe and the World.
FI is closely associated with age and is more common in residential and nursing homes affecting one in three people living in residential care and two in three nursing home residents. There is a particular therapeutic unmet need for patients with severe symptoms of FI, who are either unsuitable for, or do not wish to undergo, currently available surgical options, but who may benefit from a regenerative medical approach. There is scientific rationale and evidence that women with FI arising from obstetric anal sphincter injury, the clinical symptoms of which may appear some decades after childbirth, may most benefit from this approach and are therefore the primary target patient group in the AMELIE project. FI in postpartum women arising from obstetric sphincter injury has a reported incidence of 5.5%. In 2017, approximately 5.06 million babies were born in the European Union, suggesting ~222,640 women per annum in the EU could benefit from a regenerative medical approach.
To date, cell therapy studies using anchorage dependent cells, such as autologous skeletal muscle derived cells, are constrained by sub-optimal manufacturing techniques originally established for other purposes, prior to the advent of cell therapy. The process of detaching anchorage-dependent skeletal muscle-derived cells (SMDC) during bioprocessing and their subsequent delivery into patients as a cell suspension poses significant risks of damaging the cells through the process of anoikis (an apoptosis pathway triggered in anchorage-dependent cells when they detach from their substratum), resulting in reduced potency of the product and inconsistent response to the therapy.
To circumvent these therapeutic failings, the AMELIE consortium is developing a radical, innovative translational approach to manufacture and deliver anchorage-dependent cells into the body to establish more effective regenerative medicine therapies for FI and other clinical indications. To achieve this, we have developed a novel tissue engineered product (combined advanced therapy medicinal product) that comprises attaching the anchorage dependent cells to an implantable biodegradable, clinically qualified microcarrier. This product provides an effective substrate for cell attachment and expansion during in vitro manufacture and a system for minimally invasive, targeted in vivo delivery of cells in their natural anchored state. This will increase in vivo survival of the active component of the cell therapy after implantation, increasing the likelihood of anal sphincter regeneration.
To develop the new implantable microcarrier technology for use in regenerative medicine, the AMELIE project has the following objectives:
1. Establish new robust processes for the scalable manufacture, characterization, transportation and delivery of the implantable cell-microcarrier combination investigational product.
2. Demonstrate safety of the implantable cell-microcarrier combination investigational product using non-clinical testing to comply with national regulatory requirements and create an investigational medicinal product dossier that will enable evaluation of the technology across Europe.
3. Conduct a pan-European multi-centre, randomised, double-blind (phase I/IIb) trial to determine whether the investigation product (implantable cell-microcarrier combination) leads to a minimum clinically-relevant reduction in frequency of total FI episodes compared to control procedure.
4. Involve national and regional FI societies, patient support networks and the public throughout the project to establish suitable two-way channels for PPI activity and dissemination of project developments to patients, general public and scientific community.
5. Develop a business plan and future commercialisation strategy to enable patient access to the implantable cell-microcarrier combination across Europe and the World.
Work Package 2:
Appointment of a sub-contractor to produce TIPS microcarriers suitable for clinical use.
Continued supply of research grade TIPS microcarriers to consortium partners.
Technical transfer of the manufacturing process from UCL to the sub-contractor.
Establishment of a robust scaled-up process and production of engineering and pre-clinical batches of microcarriers that meet specifications.
Work Package 3:
Establishment of a scalable, robust process for the manufacture of SMDC attached to TIPS microcarriers.
Validation of xenogeneic(xeno)-free culture for the cell-microcarrier combination.
Validation of single-use stirred bioreactor vessels to prepare the cell-microcarrier combination.
Work Package 4:
Identification of a carrier vehicle composition compatible for mixing the microcarriers into a suspension while in the syringe.
Establishment and validation of a process to homegenously mix the microcarriers with attached cells in the carrier vehicle.
Verified integrity of the product while in storage simulating transportation to the clinical sites.
Verified cellular stability of the product when attached to the microcarriers.
Work Package 5:
Identified and assessed suitably of CROs to undertake pre-clinical testing.
Sub-contract a CRO and secured dates for the pre-clinical testing.
Planned studies and conducted technical testing in preparation for the studies.
Work Package 6:
Engaged with the Regulatory Authorities to ensure the proposed non-clinical safety data pack is suitable for regulatory compliance.
Submitted enquiries to MHRA for classification of the control intervention.
Preparation of CIP for the clinical trial.
Draft versions of other patient-facing documents.
Work Package 7:
Design and launch of the AMELIE website.
Pan-European PPI survey designed and conducted in conjunction with national charity collaborators to investigate public perception about perceptions of incontinence and the technology implantable cell-microcarrier across the European populace.
Work Package 8:
Evaluation of the IPR landscape and the incontinence market potential.
Identification of potential routes to market.
Initiation of the business case.
Appointment of a sub-contractor to produce TIPS microcarriers suitable for clinical use.
Continued supply of research grade TIPS microcarriers to consortium partners.
Technical transfer of the manufacturing process from UCL to the sub-contractor.
Establishment of a robust scaled-up process and production of engineering and pre-clinical batches of microcarriers that meet specifications.
Work Package 3:
Establishment of a scalable, robust process for the manufacture of SMDC attached to TIPS microcarriers.
Validation of xenogeneic(xeno)-free culture for the cell-microcarrier combination.
Validation of single-use stirred bioreactor vessels to prepare the cell-microcarrier combination.
Work Package 4:
Identification of a carrier vehicle composition compatible for mixing the microcarriers into a suspension while in the syringe.
Establishment and validation of a process to homegenously mix the microcarriers with attached cells in the carrier vehicle.
Verified integrity of the product while in storage simulating transportation to the clinical sites.
Verified cellular stability of the product when attached to the microcarriers.
Work Package 5:
Identified and assessed suitably of CROs to undertake pre-clinical testing.
Sub-contract a CRO and secured dates for the pre-clinical testing.
Planned studies and conducted technical testing in preparation for the studies.
Work Package 6:
Engaged with the Regulatory Authorities to ensure the proposed non-clinical safety data pack is suitable for regulatory compliance.
Submitted enquiries to MHRA for classification of the control intervention.
Preparation of CIP for the clinical trial.
Draft versions of other patient-facing documents.
Work Package 7:
Design and launch of the AMELIE website.
Pan-European PPI survey designed and conducted in conjunction with national charity collaborators to investigate public perception about perceptions of incontinence and the technology implantable cell-microcarrier across the European populace.
Work Package 8:
Evaluation of the IPR landscape and the incontinence market potential.
Identification of potential routes to market.
Initiation of the business case.
Consortium partners at QMUL, RU and UCL have contributed to a study investigating the use of cell shape characteristics as a novel profiling tool intended to identify which patients are likely to respond well to regenerative therapies. The study has evaluated the utility of multi-parametric imaging-based phenotypic characterization to distinguish the myogenic potency of SMDC. Heterogeneity in the formation of myotubes from different donors was correlated with cell shape descriptors. The results indicate that monitoring of cell shape during the early stages of bioprocessing using real-time imaging could be used to predict cellular competency necessary for differentiation and myofibre formation in vivo. This could help with selection of either patients or cell populations likely to yield better clinical outcomes in cell-based therapy for incontinence, making these therapies more cost effective. A full research manuscript has been submitted to PLOSONE journal and a research abstract submitted for presentation at ICS 2022 in Vienna.