Allogeneic Chondroprogenitor Therapy (Phase II) (ACT2)

In the UK, approximately 4.11 million people have knee osteoarthritis (OA). Consequently 98,147 total knee replacements were performed in 2016 costing £510 million, a rise of 33% in 6 years. Around 10-16,000 people require treatment for cartilage defects every year, which if untreated, can progress to OA. With effective early treatment, OA could be prevented.

The National Institute for Clinical Excellence (NICE) have stated that the most cost-effective treatment for cartilage repair is autologous chondrocyte implantation (ACI). ACI is a 2-stage process used to treat cartilage defects in the knee: an initial knee arthroscopy (key-hole surgery) is performed and a cartilage biopsy obtained. The patient's own (autologous) cartilage cells (chondrocytes) are then extracted from the biopsy and grown in the laboratory. The cells are implanted in the cartilage defect at a second surgery ~4 to 6 weeks later. NICE approved ACI in Oct-17, but there has been little adoption by NHS centres due to the regulatory constraints and challenges of an autologous product.

Chondrocytes typically do not multiply in the body and when made to do so in the lab can lose their ability to produce cartilage, one potential reason for some ACI failures. However, there is a subpopulation of cells in cartilage called Chondroprogenitors (CPs) which behave more like stem cells and have the ability to be multiplied many times over without affecting their function. We plan to use donated cartilage tissue from organ donors to obtain CPs, which will then be multiplied and implanted into cartilage defects in a single surgery. Consequently, many patients could be treated from a single donor. This could streamline NHS adoption, improve patient access & reduce morbidity in a more cost-effective way compared to standard ACI.

Key objectives of the project are:
1: Optimise CP manufacture process: Initially we will establish a safe and effective supply of donor cartilage from NHSBT. The current manufacture process will then be optimised and future proofed by removing animal sourced reagents. This will ensure efficient transfer of methodologies to the manufacturing facility (ATF) in Birmingham. Following manufacture, the cells will be frozen and stored. We will then need to determine how long we will be able to store the cells without compromising their function. An initial 6-month shelf life of the cells will be confirmed, with continued tests on-going throughout the project in order to determine the cells' maximum storage time. Quality assurance tests will be finalised to ensure the cells provided are consistent and potent. Prior to transferring protocols to the ATF the manufacture process will be independently reviewed by the Cell and Gene Therapy Catapult so as to ensure there are no apparent flaws in the process that may prevent progression to the clinical trial and future commercialisation.
2: The optimised method of cell manufacture from phase 1 of the project will be transferred to the ATF for further confirmatory tests under strict clinical conditions. The licences required from the MHRA and ethical bodies will be obtained in order for us to proceed to the clinical trial.
3: A 20 patient trial to investigate allogeneic chondroprogenitors for the treatment of isolated cartilage lesions in the knee will be performed in 3 centres: The Royal Orthopaedic Hospital, Birmingham; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry and The Nuffield Orthopaedic centre, Oxford. The primary outcome measure will be safety and Patient Reported Outcome Scores, at 3, 6, 9 & 12 months post-operatively. Secondary outcomes will be repair tissue quantity & quality on MRI scans at 12 months.

We hope that this project will address a current unmet patient need within the UK and serve as an exemplar for the development of future allogeneic cell therapies.

Standard autologous chondrocyte implantation (ACI) is a 2-stage process: an initial knee arthroscopy and cartilage biopsy followed by a second surgical implantation of expanded chondrocytes. NICE approved ACI in Oct-17, but there has been poor adoption by NHS centres due to regulatory constraints and challenges surrounding an autologous product.
We will manufacture and implant an allogeneic chondrocyte progenitor ATMP for cartilage repair in a phase II trial. This therapy could streamline NHS adoption, improve patient access & reduce morbidity in a cost-effective way compared to ACI.

Key work package objectives:

WP1: Validation of Osteochondral allograft supply chain from NHSBT in terms of cell viability and sterility. Optimised isolation, selection and tissue culture processes with future proofing by testing non-xenogeneic reagents. An initial 6-month shelf life will be confirmed via stability testing. Reference ranges for current potency markers will be set and future markers investigated by correlating levels with in-vitro chondrogenesis. The catapult will identify potential problem areas and cost savings in the manufacturing process, prior to GMP process validation

WP2: SOPs developed in WP1 will be transferred to the ATF in Birmingham for expansion, storage and delivery of allogeneic CPs. Receipt of MHRA Manufacturer's Authorisation for Investigational Medicinal Products and CTA.

WP3: A phase II, single-arm 20 patient trial to investigate allogeneic CPs for the treatment of isolated cartilage lesions in the knee. The primary outcome measure will be Serious Adverse Events and Lysholm score, at 3, 6, 9 & 12 months post-operatively. Secondary outcomes are repair tissue quantity and quality on MRI at 12 months and quality of life as measured by EQ-5D questionnaires.

This innovative project will be an exemplar and allow development of an allogeneic ATMP for which a route to reimbursement is already established.