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HIPGEN PROJECT

Disease Burden Medical Need

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


  • improve their regenerative capacities and thereby
  • improve their mobility and prevent immobility
  • prevent immobility associated diseases and survival and
  • reduce trauma/major surgery related stress reaction

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) 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.

PROJECT OBJECTIVES

HIPGEN aims at bringing the first regenerative therapy for improving recovery following a surgically treated injury to market approval.

The HIPGEN specific objectives are:


  • Confirm safety and efficacy of PLX-PAD cell therapy in patients undergoing arthroplasty for hip fracture by the mean of a randomized, double-blind, multicentre, placebo-controlled, phase III study.

  • Challenge and widen the immunomodulatory MoA, seen in a recent phase I/IIa trial, in a larger group of patients with diverse background in adaptive immunity (“immune aging”) and correlate the efficacy of the treatment to patients´ immune experience using a well standardised immune monitoring approach.

  • Evaluate to what degree the immune-mediated mechanisms exerted by the standardized PLX-PAD product in muscle regeneration depend upon the variability across the specific characteristics of the patients adaptive and innate immune responsiveness and the individual immune disbalance following trauma/major surgery stress-related response.

  • Define by in vitro and ex vivo MoA studies the PLX-PAD immune-mediated consequences on muscle tissue structure and function through a reshaped pro-regenerative environment.

  • Create a strategic engagement of the patients and family as early adopters to the cell product and foster patient and family centred care.

  • Achieve a role model for combating major trauma/surgery-related challenged immune balance in elderly patients with poor clinical outcome, like after any major surgery in elderly patients.

The successful completion of the phase III study would enable market entry in the hip fracture indication.

ORGANIZATION OF THE WORK


winkler

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.

charite
cmsc
bcrt
jwi

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 2:1 ratio into the study to receive treatment with either 150 million PLX-PAD cells or matching placebo as shown in Figure.


synopsis_wp2

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

  1. the questions to be addressed
  2. recent biomarker data from the previous clinical and preclinical studies using PLX-PAD cells
  3. the feasibility for application of the tests in a multicentre trial
pbm_wp3

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:

  • Early postoperative changes of peripheral blood immune cell composition as seen in a small phase I/IIa cohort by certified multiparameter 10-color flowcytometry (Navios, Duraclone panel) → patients of German centers and Oxford only (analyses in Berlin and Oxford).
  • Early postoperative changes in immune functionality of peripheral blood T cells by certified ex vivo functional assays (interferon-gamma Elispot[AID], cytokine secretion measured by multiplex ligand assay - Mesoscale) → patients of German centers only (analyses in Berlin).
  • Early postoperative changes in the molecular signature of peripheral blood cells as seen in a small phase I/IIa cohort by applying whole genome gene expression analysis using RNAseq → patients of all clinical centers (Berlin, Oxford, Odense, Amsterdam, Toronto, and subcontracting centres, analyses in Berlin).
  • Early postoperative changes in the molecular signature of peripheral blood cells as seen in a small phase I/IIa cohort by applying whole genome gene expression analysis using RNAseq → patients of all clinical centers (Berlin, Oxford, Odense, Amsterdam, Toronto, and subcontracting centres, analyses in Berlin).
  • Humoral alloantibody response to unmatched PLX-PAD cells analysed by Luminex platform (subcontracting HLA lab) → patients of all clinical centers (analyses in Berlin).

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:

  1. Define the PLX PAD immune-mediated mechanisms in fostering muscle regeneration through the dampening of the inflammatory environment and enhancing the anti-inflammatory, pro-regenerative environment.
  2. Define the PLX PAD paracrine mechanism modulating human muscle cell function.

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_wp4

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 GLOSSARY

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