Periodic Reporting for period 4 - RESPINE (REgenerative therapy of intervertebral disc: a double blind phase 2b trial of intradiscal injection of mesenchymal stromal cells in degenerative disc disease of the lomber SPINE unresponsive to conventional therapy)
Berichtszeitraum: 2021-07-01 bis 2023-06-30
The World Health Organization (WHO) has identified degenerative disc disease (DDD) as one of its twelve priority diseases.
Currently, there is no effective therapy for DDD, chronic cases often receive surgery, which may lead to biomechanical problems and accelerated degeneration of adjacent segments. The overall objective of the project was to assess, in a randomised clinical trial, the safety and effectiveness of an intradiscal injection of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) for the treatment of DDD. Further objectives were to provide insight into the immune response to allogeneic therapy and to understand the therapeutic mechanism.
RESPINE is a phase 2/3 prospective, multicentre, randomized, double-blind clinical trial comparing intradiscal injection of allogeneic adult BM-MSC therapy with sham treatment in subjects with chronic low back pain due to lumbar DDD unresponsive to conventional therapy. This innovative therapy aims to rapidly and sustainably reduce pain and disability. This simple procedure would be cost-effective, minimally invasive, and standardised.
In addition, the consortium aims to provide new knowledge on immune response and safety associated with allogeneic BM-MSCs intradiscal injection. Our consortium partners have developed and studied stem cell-based, regenerative therapies with encouraging results in phase 2b trials. 112 patients were included, randomized in 2 arms, sham injection or intradiscal injection of 20 X 106 allogeneic BM-MSCs. Patients were assessed at 3, 6 and 12 months for clinical response (functional score for pain, global outcome as well as impact on daily life, use of pain killers and return to work. MRI was assessed before and at 12 and 24 months after injection. During the final period, we finalized the follow up of the 112 patients and the data analysed.
Currently, there is no effective therapy for DDD, chronic cases often receive surgery, which may lead to biomechanical problems and accelerated degeneration of adjacent segments. The overall objective of the project was to assess, in a randomised clinical trial, the safety and effectiveness of an intradiscal injection of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) for the treatment of DDD. Further objectives were to provide insight into the immune response to allogeneic therapy and to understand the therapeutic mechanism.
RESPINE is a phase 2/3 prospective, multicentre, randomized, double-blind clinical trial comparing intradiscal injection of allogeneic adult BM-MSC therapy with sham treatment in subjects with chronic low back pain due to lumbar DDD unresponsive to conventional therapy. This innovative therapy aims to rapidly and sustainably reduce pain and disability. This simple procedure would be cost-effective, minimally invasive, and standardised.
In addition, the consortium aims to provide new knowledge on immune response and safety associated with allogeneic BM-MSCs intradiscal injection. Our consortium partners have developed and studied stem cell-based, regenerative therapies with encouraging results in phase 2b trials. 112 patients were included, randomized in 2 arms, sham injection or intradiscal injection of 20 X 106 allogeneic BM-MSCs. Patients were assessed at 3, 6 and 12 months for clinical response (functional score for pain, global outcome as well as impact on daily life, use of pain killers and return to work. MRI was assessed before and at 12 and 24 months after injection. During the final period, we finalized the follow up of the 112 patients and the data analysed.
During the first part of the project, the clinical study documents was approved from ethics committees and the national competent authorities in France, Italy, Spain and Germany. The clinical trial has also been registered in the international registry for clinical trials under the EudraCT number 2017-002092-25 (www.clinicaltrials.gov).
Procedures including cells expansion, cell cryopreservation and transportation of cellular treatments have been effectively optimized. The cell producer centre (beneficiary 6 / Citospin) successfully produced all batches of MSCs using bone marrow from healthy donors.
All the Standard Operating Procedures (SOP) have been drafted, and setup visits have been completed in all nine clinical centres across France (4 centres), Italy (1 centre), Spain (3 centres) and Germany (1 centre). The first patients enrolled in the RESPINE trial received their injections in March 2019. By May 2021, a total of 112 expected patients had undergone treatment with either allogeneic adult BM-MSCs therapy or a sham treatment. The execution of logistical processes, including the timely transport of cells from the cellular production centre to various clinical centres and the centralized reading validation of MRI scans for patient inclusion, proceeded without any significant setbacks.
During the last period, all patients completed visits at months 6, 12, and 24, and the RESPINE clinical trial ended in April 2023. No Serious Adverse Events (SEAs) with life-threatening impact were noted. The overall benefit/risk ratio remained positive throughout the treatment period. Remarkably, 74% of patients experienced improvement in both pain and functional scores, although the study did not reach the primary endpoint. Clinical improvements were observed in pain scores as well as in mental scores (SF36) at the 12-month.
In parallel, immune response analyses were conducted, measuring anti HLA antibodies in the serum of 50 BM-MSCs-treated patients at both month 0 and month 6. Positive cases were further characterized to identify donor-specific antibodies (DSA). A robust, reproducible, and accurate growth factor-based induction protocol was established to generate nucleopulpocyte like cells from human BM-MSCs.
The RESPINE team has disseminated findings through 5 publications in peer-reviewed journals and press articles. The final publication on clinical results is currently under review. Throughout the RESPINE project, the consortium shared its results at various international congresses. A comprehensive presentation of all results took place during the final workshop held in Montpellier on 13th June 2023.
Procedures including cells expansion, cell cryopreservation and transportation of cellular treatments have been effectively optimized. The cell producer centre (beneficiary 6 / Citospin) successfully produced all batches of MSCs using bone marrow from healthy donors.
All the Standard Operating Procedures (SOP) have been drafted, and setup visits have been completed in all nine clinical centres across France (4 centres), Italy (1 centre), Spain (3 centres) and Germany (1 centre). The first patients enrolled in the RESPINE trial received their injections in March 2019. By May 2021, a total of 112 expected patients had undergone treatment with either allogeneic adult BM-MSCs therapy or a sham treatment. The execution of logistical processes, including the timely transport of cells from the cellular production centre to various clinical centres and the centralized reading validation of MRI scans for patient inclusion, proceeded without any significant setbacks.
During the last period, all patients completed visits at months 6, 12, and 24, and the RESPINE clinical trial ended in April 2023. No Serious Adverse Events (SEAs) with life-threatening impact were noted. The overall benefit/risk ratio remained positive throughout the treatment period. Remarkably, 74% of patients experienced improvement in both pain and functional scores, although the study did not reach the primary endpoint. Clinical improvements were observed in pain scores as well as in mental scores (SF36) at the 12-month.
In parallel, immune response analyses were conducted, measuring anti HLA antibodies in the serum of 50 BM-MSCs-treated patients at both month 0 and month 6. Positive cases were further characterized to identify donor-specific antibodies (DSA). A robust, reproducible, and accurate growth factor-based induction protocol was established to generate nucleopulpocyte like cells from human BM-MSCs.
The RESPINE team has disseminated findings through 5 publications in peer-reviewed journals and press articles. The final publication on clinical results is currently under review. Throughout the RESPINE project, the consortium shared its results at various international congresses. A comprehensive presentation of all results took place during the final workshop held in Montpellier on 13th June 2023.
RESPINE pursued three main goals that were nearly accomplished:
Our primary goal was to validate a novel biological treatment approach for Degenerative Disc Disease (DDD), a major health and societal challenge with limited success from conventional treatments. Our Consortium has successfully completed the clinical trial, demonstrating clinical improvement in pain scores. The intradiscal injection of allogeneic BM-MSCs has been confirmed as a safe procedure. Ongoing research is investigating the long-term outcomes of BM-MSC therapy for DDD. It is crucial to evaluate the durability of the results and determine whether additional treatments or maintenance injections may be necessary. This progress brings us closer to offering a more effective and sustainable solution for individuals dealing with DDD.
Our secondary goal was to develop a potency test that can predict the effectiveness of the treatment, allowing us to anticipate future industrial development. This involves identifying specific biomarkers to monitor the biological activity of BM-MSCs and evaluating the immune response when using allogeneic cells. In this regard, several anti-inflammatory molecules were identified as part of the secretome of MSCs that can be validated as components of the therapeutic mechanism and may find use as potency markers.
The final goal was to develop innovative therapies for the broader European population and have the potential for future commercialization. Our consortium, with extensive experience in manufacturing cell therapy products, played a crucial role in successfully completing the RESPINE project. This project demonstrated the feasibility of producing allogeneic BM-MSCs, preserving them through cryopreservation, and revitalising them for injection in clinical trials. The clinical results are encouraging to proceed with further clinical trials, not only for this particular application but also for other potential uses.
Our primary goal was to validate a novel biological treatment approach for Degenerative Disc Disease (DDD), a major health and societal challenge with limited success from conventional treatments. Our Consortium has successfully completed the clinical trial, demonstrating clinical improvement in pain scores. The intradiscal injection of allogeneic BM-MSCs has been confirmed as a safe procedure. Ongoing research is investigating the long-term outcomes of BM-MSC therapy for DDD. It is crucial to evaluate the durability of the results and determine whether additional treatments or maintenance injections may be necessary. This progress brings us closer to offering a more effective and sustainable solution for individuals dealing with DDD.
Our secondary goal was to develop a potency test that can predict the effectiveness of the treatment, allowing us to anticipate future industrial development. This involves identifying specific biomarkers to monitor the biological activity of BM-MSCs and evaluating the immune response when using allogeneic cells. In this regard, several anti-inflammatory molecules were identified as part of the secretome of MSCs that can be validated as components of the therapeutic mechanism and may find use as potency markers.
The final goal was to develop innovative therapies for the broader European population and have the potential for future commercialization. Our consortium, with extensive experience in manufacturing cell therapy products, played a crucial role in successfully completing the RESPINE project. This project demonstrated the feasibility of producing allogeneic BM-MSCs, preserving them through cryopreservation, and revitalising them for injection in clinical trials. The clinical results are encouraging to proceed with further clinical trials, not only for this particular application but also for other potential uses.