Periodic Reporting for period 4 - BIO-CHIP (BIOengineered grafts for Cartilage Healing In Patients (BIO-CHIP))
Período documentado: 2019-11-01 hasta 2020-10-31
Knee articular cartilage injuries cause pain, lead to poor joint function and disability. The spontaneous healing of cartilage lesions is poor and their treatment is still a challenge for orthopedic surgeons. If left untreated, these lesions may predispose to osteoarthritis and ultimately total joint replacement.
Cartilage repair procedures have the potential to relieve pain, improve the quality of life in younger patients and may delay or eliminate the need for joint replacement in the elderly. However, current treatments still have major drawbacks such as poor quality of repair tissue in comparison to native cartilage. The implantation of autologous articular chondrocytes (AC, cells harvested from a small biopsy of the patient’s own knee cartilage) at the damaged site to induce cartilage regeneration has represented a major breakthrough in the field. However, probably due to the variable quality of the cells used, even these treatments cannot yet offer predictable, reproducible and durable restoration of cartilage structure and function.
The BIO-CHIP project introduces two innovations with the potential to improve the clinical outcome of cartilage repair:
• use of a different source of cells: cells (Nasal Chondrocytes, NC) are harvested from the nasal septum of patients with limited risk of donor-site morbidity. Moreover, NC have been shown to have a higher and more reproducible capacity to regenerate cartilage tissue than AC. Additionally, NC can adapt to the joint environment acquiring the expression of molecules characteristic of AC and can withstand mechanical forces associated with weight bearing as well as inflammation associated with trauma and surgery;
• engineering of a mature cartilage tissue: the NC-based implant can be developed to various degrees of functional maturation depending on the culture time. In particular, NC,-based grafts can reproducibly reach biochemical and mechanical maturation approaching that of native cartilage, in contrast to typical tissues engineered using AC. A more mature tissue could offer higher functionality upon implantation and superior long-term performance, though this hypothesis has never been clinically tested.
The BIO-CHIP project targets two main objectives:
• conduct a multicenter (Croatia, Germany, Italy and Switzerland), prospective, phase II clinical study to treat 108 patients to determine the effect of maturation of NC-based cartilage grafts on the clinical outcome;
• explore in a large animal model the possibility to extend the clinical indications of the engineered grafts from acute, traumatic cartilage injuries to currently untreatable, degenerative cases (pre-osteoarthritic lesions).
In the multicenter clinical trial, 100 of 108 patients could be included, thus reaching the critical number of 97 patients, statistically required according to a power analysis to reach the objective of the study. Follow-up of patients is still ongoing, so no conclusion about the effect of maturation can be drawn yet. However, preliminary results indicate that most patients could benefit from the treatment. Animal experiments have shown, that grafts are also applicable in biomechanically challenging indications, such as kissing lesions. This is currently a contraindication for all cartilage repair products on the market.
Cartilage repair procedures have the potential to relieve pain, improve the quality of life in younger patients and may delay or eliminate the need for joint replacement in the elderly. However, current treatments still have major drawbacks such as poor quality of repair tissue in comparison to native cartilage. The implantation of autologous articular chondrocytes (AC, cells harvested from a small biopsy of the patient’s own knee cartilage) at the damaged site to induce cartilage regeneration has represented a major breakthrough in the field. However, probably due to the variable quality of the cells used, even these treatments cannot yet offer predictable, reproducible and durable restoration of cartilage structure and function.
The BIO-CHIP project introduces two innovations with the potential to improve the clinical outcome of cartilage repair:
• use of a different source of cells: cells (Nasal Chondrocytes, NC) are harvested from the nasal septum of patients with limited risk of donor-site morbidity. Moreover, NC have been shown to have a higher and more reproducible capacity to regenerate cartilage tissue than AC. Additionally, NC can adapt to the joint environment acquiring the expression of molecules characteristic of AC and can withstand mechanical forces associated with weight bearing as well as inflammation associated with trauma and surgery;
• engineering of a mature cartilage tissue: the NC-based implant can be developed to various degrees of functional maturation depending on the culture time. In particular, NC,-based grafts can reproducibly reach biochemical and mechanical maturation approaching that of native cartilage, in contrast to typical tissues engineered using AC. A more mature tissue could offer higher functionality upon implantation and superior long-term performance, though this hypothesis has never been clinically tested.
The BIO-CHIP project targets two main objectives:
• conduct a multicenter (Croatia, Germany, Italy and Switzerland), prospective, phase II clinical study to treat 108 patients to determine the effect of maturation of NC-based cartilage grafts on the clinical outcome;
• explore in a large animal model the possibility to extend the clinical indications of the engineered grafts from acute, traumatic cartilage injuries to currently untreatable, degenerative cases (pre-osteoarthritic lesions).
In the multicenter clinical trial, 100 of 108 patients could be included, thus reaching the critical number of 97 patients, statistically required according to a power analysis to reach the objective of the study. Follow-up of patients is still ongoing, so no conclusion about the effect of maturation can be drawn yet. However, preliminary results indicate that most patients could benefit from the treatment. Animal experiments have shown, that grafts are also applicable in biomechanically challenging indications, such as kissing lesions. This is currently a contraindication for all cartilage repair products on the market.
The clinical study “Nose to Knee II” is carried out in 5 centers under approval of the respective ethical committees and national authorities.
So far, grafts satisfying the defined specifications have successfully been manufactured for all but two patients and shipped to the respective clinical sites. New quality control assays to assess cell viability (non-destructive) as well as identity and potency have been developed.
So far, only one serious adverse reaction was detected in 100 treated patients. Two patients had to be excluded intraoperatively from the study due to more severe lesions than originally anticipated or comorbidities and two were excluded due to a failed graft manufacturing. The collected data are regularly monitored in a harmonized manner to ensure correct and complete documentation and respect of patients' rights as per international guidelines.
100 patients have been treated by November 2020. 65 and 23 patients have completed respectively the 12 and 24 months follow up. Even though no conclusions can be drawn yet due to the limited number of patients, most patients seem to benefit from the treatment as indicated by an increase of more than 10 points of the clinical scores from the self-assessed validated questionnaires Knee injury and Osteoarthritic Outcome Scores (KOOS). Moreover, also the assessment of the Magnetic Resonance Imaging (MRIs) 12 and 24 months postoperative indicated that all grafts were in place and integration with the adjacent cartilage was ongoing.
Alongside the clinical and manufacturing issues, the future market potential of the products has been considered through an analysis of current and future clinical indications, treatments and their respective costs. Two strategies for future commercialization have been identified. In Switzerland a scientific advice meeting with authorities has indicated, that application for marketing authorization could be possible for defects larger than 4cm2. A temporary authorization has been issued for the treatment of specific cartilage defects outside of the study. For the European Market the application for hospital exemption (local authorization for this state) is ongoing for Germany and Croatia.
To extend the range of clinical indications to currently untreatable diseases such as osteoarthritis, a large animal study has been performed to evaluate the suitability of the engineered cartilage grafts in kissing lesions facing each other on both sides of the knee joint, which are considered as (pre)osteoarthritic. Results show good retention and integration of the implanted grafts as well as an improved quality of the repair tissue from 6 weeks to 6 months post implantation. Inflammatory responses detected after 6 weeks decreased over time and although the remodelling process was still ongoing after 6 months, promising results can be expected in the long term. The results of this study demonstrate that the treatment with a nasal cartilage graft is suitable for this indication and phase I trial could be performed in patients with pre-osteoarthritic lesions based on these preclinical data.
A number of scientific presentations and articles in the popular press have targeted both the medical community and the public. A website (http://biochip-h2020.eu/) describes the project and several national and international trial databases (clinicaltrials.gov identifier NCT02673905) offer relevant information to potential patients and the public community.
So far, grafts satisfying the defined specifications have successfully been manufactured for all but two patients and shipped to the respective clinical sites. New quality control assays to assess cell viability (non-destructive) as well as identity and potency have been developed.
So far, only one serious adverse reaction was detected in 100 treated patients. Two patients had to be excluded intraoperatively from the study due to more severe lesions than originally anticipated or comorbidities and two were excluded due to a failed graft manufacturing. The collected data are regularly monitored in a harmonized manner to ensure correct and complete documentation and respect of patients' rights as per international guidelines.
100 patients have been treated by November 2020. 65 and 23 patients have completed respectively the 12 and 24 months follow up. Even though no conclusions can be drawn yet due to the limited number of patients, most patients seem to benefit from the treatment as indicated by an increase of more than 10 points of the clinical scores from the self-assessed validated questionnaires Knee injury and Osteoarthritic Outcome Scores (KOOS). Moreover, also the assessment of the Magnetic Resonance Imaging (MRIs) 12 and 24 months postoperative indicated that all grafts were in place and integration with the adjacent cartilage was ongoing.
Alongside the clinical and manufacturing issues, the future market potential of the products has been considered through an analysis of current and future clinical indications, treatments and their respective costs. Two strategies for future commercialization have been identified. In Switzerland a scientific advice meeting with authorities has indicated, that application for marketing authorization could be possible for defects larger than 4cm2. A temporary authorization has been issued for the treatment of specific cartilage defects outside of the study. For the European Market the application for hospital exemption (local authorization for this state) is ongoing for Germany and Croatia.
To extend the range of clinical indications to currently untreatable diseases such as osteoarthritis, a large animal study has been performed to evaluate the suitability of the engineered cartilage grafts in kissing lesions facing each other on both sides of the knee joint, which are considered as (pre)osteoarthritic. Results show good retention and integration of the implanted grafts as well as an improved quality of the repair tissue from 6 weeks to 6 months post implantation. Inflammatory responses detected after 6 weeks decreased over time and although the remodelling process was still ongoing after 6 months, promising results can be expected in the long term. The results of this study demonstrate that the treatment with a nasal cartilage graft is suitable for this indication and phase I trial could be performed in patients with pre-osteoarthritic lesions based on these preclinical data.
A number of scientific presentations and articles in the popular press have targeted both the medical community and the public. A website (http://biochip-h2020.eu/) describes the project and several national and international trial databases (clinicaltrials.gov identifier NCT02673905) offer relevant information to potential patients and the public community.
The development of a successful therapy for cartilage lesions would have strong implications for patients suffering from cartilage damages, including a positive effect on the quality of life through a reduction of pain and increased mobility, and a potential delay in the onset of degenerative cartilage diseases with associated need for joint replacement. In turn, this clinical outcome would have relevant consequences in the global reduction of healthcare costs.