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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

Periodic Reporting for period 2 - 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)

Reporting period: 2018-07-01 to 2019-12-31

WHO has included low back pain in its list of twelve priority diseases and notably, degenerative disc disease (DDD). Today, no efficient therapy is available for DDD. Chronic cases often receive surgery, which may lead to biomechanical problems and accelerated degeneration of adjacent segments. Our consortium partners have developed and studied stem cell-based, regenerative therapies with encouraging results in phase 2b trials. Patients exhibited rapid and progressive improvement of functional and pain indexes by 50% within 6 months and by 65% to 78% after 1 year with no severe side effects. In addition, MRI T2 relaxation measurements demonstrated a significant improvement. To develop the world’s first rigorously proven, effective treatment of DDD, RESPINE aims to conduct a clinical trial: a phase 2/3 prospective, multicentre randomized, double-blind trial, comparing intra-discal allogeneic adult BM-MSCs therapy and sham-treated controls in subjects with chronic low back pain due to lumbar degenerative disc disease (DDD) unresponsive to conventional therapy. This innovative therapy aims to rapidly (within 3 months) and sustainably (at least 24 months) reduce pain and disability. In addition, the consortium aims to provide new knowledge on immune response and safety associated with allogeneic BM-MSCs intradiscal injection. This simple procedure would be cost-effective, minimally invasive, and standardised.
The clinical study protocol as well as IMPD and all regulatory dossiers have been submitted to the EU regulatory agency (EMA) through VHP, after receiving the appropriate Ethical Approvals by local competent ethics committees and the national competent authorities in France, Italy and Spain. However, in Germany, the national competent authority decided to continue the VHP process and requested thus to extend follow-up for the German patients (5 years instead of 2 years in the protocol). The Clinical trial has been registered in the international registry for clinical trials under the number NCT03737461 (www.clinicaltrials.gov).

Optimization of cellular treatment transport, improvement of cell expansion steps and cellular cryopreservation have been fully achieved. All these tasks are described in all the documentation required for the submission of the VHP (Voluntary Harmonized Procedure) application. Those informations are also included in the Investigational Medicinal Product Dossier (IMPD) and the Investigative Brochure (IB). The cell producer center (beneficiary 6 / Citospin / CSP) has produced all the batches of MSCs from healthy donors’ bone marrow. The resulting cryogenic MSCs stock will be used to perform the entire RESPINE trial. Each cell syringe used for treatment holds 20 million MSCs at the concentration of one million cells per millilitre.

Due to regulatory delay of the VHP procedure and specific request of PEI, the implementation of the clinical trial was delayed for 6 months. Currently, all the Standard Operating Procedures (SOP) have been drafted and the setup visits have been done in eight clinical centers out of nine: France (4 centres), Italy (1 centre), Spain (3 centres). The first patients of the RESPINE trial were injected in March 2019, and, by December 2019, over 50 patients had been screened and 36 patients had been injected.
The first report has been drafted and sent to the safety Board and we expect to receive feedback around March 2020. Pharmacovigilance/monitoring analyses, which include, among others, immune response surveillance assays, hold a central and essential role in this clinical trial.
The follow-up of the injection will be monitored closely, in order to detect any trace of immune response against the graft; this objective will be described in the deliverable 4.6 which was delayed because of the inclusion status.

Excellent progress has been made in fulfilling the objectives outlined for WP5, thus the following significant results were achieved:
We established a reproducible, robust and accurate growth factor-based induction protocol to generate nucleopulpocyte-like cells from human MSCs. In this protocol, the amplification phase was performed in 2D in a humid chamber at 37°C in normoxic condition in the presence of DMEM and cultivated without FCS during 28 days in the presence of nucleopulpogenic medium (NP) composed of DMEM supplemented with 1% P/S, sodium L-ascorbate (50 nM), human insulin-transferrin-sodium selenite (ITS; insulin: 6.25 µg/ml, transferrin: 6.25 μg/ml, sodium selenite: 6.25 ng/ml), TGF-1 (10 ng/ml) and recombinant human GDF5 (100 ng/ml). This protocol was performed on 3 samples and the correlation with clinical results will be performed at the end of the trial.
miRNAs are a new class of molecules that have been associated with the immunomodulatory function of ASCs. Some miRNAs, such as miR-146a or miR-155, have already been identified as playing a role in this function and targeting different immune cell subtypes. We propose that our new miRNA signature could be identified and used as diagnostic, prognostic, or predictive biomarkers in regenerative medicine and used as a potency assay for BM MSCs.
Our primary goal is to validate a novel therapeutic approach for DDD, a major health and societal problem, for which the conventional treatments results are poor. Our proposal has solid basis based on consortium members’ previous research, which include, not only basic research, but also phase 2a clinical trials in DDD.
In this trial, we have the ambition to use freshly released allogeneic cells from a cGMP facility to the multiple clinical sites. This requires logistic steps that have been taken into account by consortium members. The cGMP manufacturing companies (Citospin) and UniverCell Biosolution, through previously validated standard procedures in the shipment of cGMP, produce cells for cellular therapeutic applications.

The secondary goal is to develop potency test predictive of efficacy, in order to anticipate future industrial development, notably by identifying biomarkers to follow intradiscal MSCs biological activity and assess the allogeneic immune response.

The final goal after validation of the cell product and clinical trial efficacy is to develop innovative therapies for large EU population and to be able to commercialize the product in the future. The consortium has extensive experience in manufacturing cell therapy products, which enables the identification of the main challenges in the industrialization of regenerative medicine. To address them, strong focus on pursuing new manufacturing strategies will be done for allogeneic cell production. This approach will also contribute to reduce manufacturing costs. Production improvements will be faced through researching optimization of the production and transport protocols as well as cryopreservation. Participation of two SMEs that are pioneers in this area will help to deliver the new solutions to the market and to compete in optimal conditions. Throughout the project, we will be attentive to regularly review and take measures to protect the IP. In case the clinical results are encouraging, RESPINE will develop this innovative medical product, including quality controls, traceability and safety in order to be approved by the EU market and to achieve reimbursability in the future.
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