Hip fractures are defined as fractures of the proximal femur, among them neck of femur fractures and per- or subtrochanteric fractures, both constituting half of all hip fractures. In Europe, roughly 50% of all neck of femur fractures are surgically treated with an internal fixation device, mostly gliding screws, however, this is prone to a high complication and revision rate (15% non-fusion). This is the reason why increasingly more neck of femur fractures are treated with hemi- (HA) or total arthroplasty (THA), allowing for immediate total weight bearing mobilisation, which should be life saving for these patients. Nevertheless, mortality rates of these frail patients treated with internal fixation and arthroplasty are the same. The reasons for this are damage resulting from joint exposition during arthroplasty, poor regeneration capacity, immunological stress due to the trauma and consecutive surgery Hence, the death rate of hip fracture patients is comparable to malignant diseases with a 1-year mortality rate of 25% - 30 %. As a consequence, there is a high need for the development of a new therapeutic option for these patients in order to
To date, no therapeutic option exists other than adjustments in the general set-up for the patients suffering from hip fracture, e.g. rehabilitation procedures.
We propose a new innovative therapy, which is in advanced clinical development stage: allogeneic placental cell therapy with PLX-PAD cells (→ more→ less) for the enhanced recovery following hip fracture surgery. Within this project, we will perform a multi-center phase III clinical study with 240 patients. Internationally renowned European orthopaedic and trauma centres will be partners in the trial (University of Oxford, Odense University Hospital) and further renowned clinical centres and hospitals will be included in the trial. As a catalyst for improved patient engagement, an innovative patient platform implemented by Be the Partner will be used for the first time in an ATMP trial.
PLX-PAD cells are an allogeneic “off-the-shelf” cell product, that is in advanced development towards marketing application in patients with hip fractures.
PLX-PAD cells are placenta-expanded stromal cells with a variety of regenerative and immunomodulating properties, which have been revealed and analysed profoundly in preclinical and clinical studies. In particular, positive effects on postoperative immunological stress reaction and in parallel improved skeletal muscle regeneration and strengthening could be observed.
HIPGEN aims at bringing the first regenerative therapy for improving recovery following a surgically treated injury to market approval.
The HIPGEN specific objectives are:
The successful completion of the phase III study would enable market entry in the hip fracture indication.
The HIPGEN consortium is coordinated by the Charité Berlin. The project coordinator is Dr. Tobias Winkler, senior scientist and physician from the Centre for Musculoskeletal Surgery (CMSC) & Julius Wolff Institute (JWI) Berlin, is a specialist in orthopaedic surgery with a focus on arthroplasty and trauma and is heading the Unit for Muskuloskeletal Cell Therapy at the CMSC and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT) of the Charité.
HIPGEN brings together partners with excellent expertise in the fields of cell therapy and clinical research on orthopaedic studies.
The specific objectives of HIPGEN will be achieved in seven work packages:
WP1 Manufacturing of PLX-PAD product(s) deals with the manufacturing and quality control analyses of the investigational cell product, PLX-PAD, and will be performed in the approved GMP facility and QC laboratories of Pluristem. The Pluristem team (headed by Racheli Ofir) will bring in its first-in-class IP-protected manufacturing process for expansion of PLX-PAD cells, including the surrounding QC expertise. This process can produce sufficient numbers of clinical grade IP. The PLX-PAD cell product will consist of >90% maternal cells (X/X karyotype). It is expected to use batches (bioreactor runs) from 1 placenta donor.
WP2 HIPGEN phase III clinical trial: PLX PAD for recovery following surgery for hip fracture WP2 is the core activity of the project. The multicentre Phase III study is planned to assess PLX-PAD efficacy, safety and tolerability of PLX-PAD intra-muscular injections for improved recovery following arthroplasty for Hip Fracture (HF). 240 subjects will be randomized in a 1:1 ratio into the study to receive treatment with either 150 million PLX-PAD cells or matching placebo as shown in Figure.
Synopsis of the Proposed Clinical Trial
WP3 Biomarker analysis of PLX-PAD treated HIPGEN patients focuses on the accompanying biomarker program in the study patients. The panel was designed by Berlin, (HD Volk, P Reinke, T Winkler) and will be performed in collaboration with UOXF. The biomarkers and the biomarker study design is based on
Platforms for Biomarker Monitoring (WP3)
The different tests of the 4 platforms were selected based on preliminary work and are well established and validated for clinical monitoring.
The panel goes far beyond typical standard laboratory markers, and addresses several questions by applying immunological and molecular technologies to reveal the impact of PLX-PAD therapy on the immune system and hence on the regenerative capacity of the patients All tests are well established and validated in the certified biomarker study lab of Charité:
WP4 Immune-mediated and paracrine mechanisms of action of PLX-PAD in muscle regeneration
In muscle injury, inflammation plays an important role in determining the success or failure of tissue regeneration. This workpackage is organized in two main activities WP4A and WP4B toward the obtainment of the following objectives:
WP4A will be conducted on the cross-talk between PLX-PAD cells (same batches as for the treatment) and peripheral blood mononuclear cells (PBMC) isolated from healthy subjects at different ages and from a sub-cohort of patients before treatment with PLX-PAD (Berlin).
We will provide an understanding of PLX PAD immune-mediated mechanisms in fostering muscle regeneration by studying the modulation of inflammatory cells and cytokines involved in the dampening of the inflammatory environment (pro-inflammatory cytokines, M1 macrophages, and cytotoxic T cells and neutrophils), and enhancing the resolution process (anti-inflammatory cytokines, regulatory M2 and T cells).
Within WP4B we aim to systematically investigate the beneficial effects of PLX PAD cells on the cellular function of human skeletal muscle myoblasts from healthy donors at different ages and from HIPGEN patients before treatment with PLX-PAD (Berlin).
Synopsis of the strategy employed in this study to identify the mode of action (MoA) by which PLX PAD improve muscle regeneration
This study assumes that MoA of PLX PAD is based on the induction of a pro-inflammatory to anti-inflammatory shift (with a decrease of Th1 and M1 and increase of Treg and M2), a direct paracrine stimulation of muscle myoblast function or a combination thereof. Given that both endogenous regeneration capacity and immune cell function is related to age, this study will be conducted on skeletal muscle myoblasts and immune cells from patients and age matched healthy subjects.
WP5 Creation and use of the Be the Partner platform for strategic engagement
Leaded by Be the Partner AG, a SME involved for the first time in a H2020 project, that will implement a patient platform to engage, retain and inform study participants and their caregivers during the trial. The Be the Partner platform also serves as a patient registry when patients have completed the clinical trial. This patient registry will provide long- term connectivity with trial alumni for future trials or surveying the patients to gather additional feedback.
WP6 Project Management and Coordination
We ensure efficient operational management including that of administrative, financial and legal issues The goal of this WP is to establish and guarantee full synergy, motivation, integration and effective interactions among HIPGEN participants.
WP7 Communication, dissemination, training and exploitation
Leaded by ALTA in collaboration with Charité this WP aim to set up of the proper tools and activities of communicating the project results and new achievement to the general public and patients, and to the clinical and scientific community.
The International Osteoporosis Foundation (IOF) is partner of the HIPGEN consortium. The involvement of patients and the consideration of their views and needs is a very important part of the HIPGEN project. We believe that patients’ opinions are very important in the development of new therapies for frail patients. The patient´s position within the trial will not only be strengthened by the Be the Partner platform but also by the participation of the IOF. The role of IOF will be, among others, to provide patient’s views with respect to the development of the therapeutic approach of the study, raise awareness in the society and political fora about the project topic, increase awareness about development of specific new strategies for management of hip fracture, raise attention about how to improve access to most appropriate care, and reduce social burden. IOF will ensure communication and dissemination of the scientific findings to a global healthcare professional audience, researchers, policy makers and patients through our extensive database (> 25,000 recipients) with an interest in the field of bone health via web blast, on the IOF website, and via social media channels. Through its 240 national societies, IOF has an important network of patient societies in Europe and worldwide. In case of a success of our phase III study and market approval for the product, the dissemination of the knowledge about the first product for hip fracture recovery and survival will be perfectly supported by the resources of the IOF, in particular also its close interaction with national and international patient interest groups.
Project status after 18 months
State of art
The HIPGEN project aims at bringing the first regenerative therapy for improving recovery following a surgically treated injury to market approval. HIPGEN proposes a new innovative therapy, which is in advanced clinical development stage: allogeneic placental cell therapy with PLX-PAD cells for the enhanced recovery following hip fracture surgery. The focus of the HIPGEN trial are patients undergoing total or hemiarthoplasty after femoral neck fracture. These fractures are a major public health concern in the EU with an increasing incidence of 1 million patients per year, high direct and indirect costs due to the resulting immobility after fracture and surgery, and a mortality comparing to cancer with up to 30% during the first year. The elderly patients are massively challenged by the incidence of injury and the consequent surgery and exhibit a very low regenerative capacity. No therapy is currently available to address the problem of impaired regeneration and mobility and the risks, including the high mortality, after hip fracture surgery.
Work performed & expected results
Within the reporting period, we prepared and started a randomized, double-blind, multicentre, placebo-controlled phase III trial for restoring muscle function, mobilisation and reduction of post-operative stress-related immune disbalance in hip fracture patients treated with placenta-expanded adherent stromal cells (PLX-PAD cells) after arthroplasty. By these regenerative mechanisms, we also aim at improving the survival of these patients.
The initial phase of the project included preparation, submission and finalisation of all study documents. Clinical grade PLX-PAD batches were successful manufactured and used/stored for the patients’ treatment and sent for accompanying in-depth characterisation to the partners. As of June 2019, 76 patients were found eligible for randomization into the trial. Currently 19 sites are active in Europe, Israel and in the US. The study patients will be investigated to identify surrogate biomarkers and to reveal paracrine as well as immune-mediated mechanisms of actions of PLX-PAD on muscle regeneration. The preparatory tasks for these analyses have also been finished and approvals have been received. These mechanistical side studies help to understand the mode-of-action of the applied therapy. To keep patients engaged during the trial, a HIPGEN-specific ‘Be the Partner’ platform has been created and launched. In addition to the scientific progress, the overall awareness of Advanced Therapies in hip fracture patients and the HIPGEN project itself increased due to diverse dissemination activities by all partners, for example via social media, scientific and public presentations/posters as well as video interviews with the PI and project coordinator, the latter will be available soon on the HIPGEN and International Osteoporosis Foundation (IOF) website.
The HIPGEN-project generates comprehensive in depth understanding on the immunomodulatory and muscle trophic modes of action in a large and relevant patient cohort; thereby establishing a role model in the ground-breaking regenerative therapeutic field of Advanced Therapies by providing advanced business and reimbursement models.
THA total hip arthoplasty
HA hemi arthoplasty
FNF femur neck fracture
PLX- PAD cells PLacenta-eXpanded stromal cells optimized to support regeneration from Peripheral Arterial Disease
EMA European Medicinal Agency
FDA Food and Drug Administratio
ATMP Advanced Therapy Medicinal Product