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HIPGEN HOME


The HIPGEN project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779293

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The HIPGEN project aims at bringing the first regenerative therapy for improving recovery following a surgically treated injury to market approval. The major focus of the HIPGEN are patients undergoing to total or hemiarthoplasty after hip fracture (→ less).

Hip 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 consecutive surgery and exhibit a very low regenerative capacity. No therapy is currently available to address the problem of impaired regeneration and mobility and the consequences, including the high mortality, after hip fracture surgery.


hip_fracture

Picture from the National Library of Medicine nlm.nih.gov

• ALL patients are surgically treated
• Europe: hemiarthroplasty (HA): internal fixation (IF) 50:50
• USA: more HA than IF
• Data show high revision rate in IF cases due to non-union

→ close


hip_ha_if

HA Hip bipolar head picture from Aesculap Implants System
IF Dynamic hip screw picture from De Puy Synthes


Problem of surgical interventions: Intraoperative muscle trauma on top of damage-predisposing sarcopenia in elderly patients → impaired mobilization + surgical stress in frail patients → high mortality.


therapy_cell_product

Picture from Sein letztes Rennen, BR, Universum Film GmbH 2013

Therapy Cell product: PLX-PAD

feet_walking

We will conduct a multicentre phase III clinical study assessing the improvement of restoring muscle function, mobility and the reduction of post-operative stress-related immune disbalance in hip fracture patients treated with placenta-expanded adherent stromal cells (PLX-PAD cells → more) after arthroplasty.

By these regenerative mechanisms, we also aim at improving the survival of these patients.

Within the study we will confirm the safety and promising efficacy phase I/II data from patients undergoing total hip arthroplasty, and we enhance our understanding on the mode-of-action (MoA) of PLX-PAD.

HIPGEN partners are world-leading experts in orthopaedic surgery or rehabilitation, clinical immunology and performing innovative clinical studies, 3D-cell manufacturing , preclinical and clinical cell therapy and biomarker analyses.

HIPGEN NEWS

 

2018
19June

HIPGEN website online

25April

U.S. Food and Drug Administration (FDA) has cleared Pluristem’s Investigational Drug Application (IND) of its PLX-PAD cell therapy for HIPGEN study
More on → Press releases

14Jan

HIPGEN KICK OFF MEETING, Berlin - BCRT Charité
More on → Events

HIPGEN PROJECT

Disease Burden Medical Need

PROJECT | OBJECTIVES | ORGANIZATION | GLOSSARY

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.




PLX-PAD CELLS

Source and Manifacturing

PLX-PAD, an allogeneic cell-based dispersion for injection and classified as an Advanced Therapy Medicinal Product (ATMP), is comprised of ex-vivo expanded placental adherent stromal cells that are derived from human placentae. The placentae are collected from healthy women undergoing elective Caesarean section. The placenta donors sign an informed consent form and are not compensated for this donation. No ethical issues are known to exist in the use of placenta derived stromal cells.

PLX-PAD cells are manufactured, packaged and labelled by Pluristem Ltd. in GMP-compliant facilities located in Haifa, Israel. The PLX-PAD cell expansion manufacturing process consists of two stages.


plx_products

Schematic manufacturing process for the two major PLX products.

The first stage consists of isolating the adherent stromal cells from a placenta and the expansion of these cells by 2-dimensional growth to produce the intermediate cell stock. During the second stage, the intermediate cell stock is thawed and undergoes further culture expansion using 2- and 3- dimensional growth to produce the PLX-PAD drug substance. PLX-PAD cells have a population doubling level limited to no more than 25 from the original extraction of placental cells until cryopreservation of the final cell product. If passaged in vitro, the final PLX-PAD cells reach senescence within ~37 additional population doublings while maintaining a stable karyotype.

PLX-PAD cells are provided as a frozen cell dispersion in cryogenic vials containing 6 mL, at a cell concentration of either 10 million cells/mL or 20 million cells/mL in a solution containing 10% (v/v) dimethyl sulfoxide (DMSO), 5% (w/v) human serum albumin (HSA) in Plasma-Lyte A. PLX-PAD is stored in the vapor phase of liquid nitrogen below -150°C. The shelf life of the product is currently 36 months and ongoing stability studies aim to allow its’ extension.

It is essential to underline that the production process is industrially scalable and already EMA and FDA approved.

CLINICAL STUDY

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study, Designed to Determine the Efficacy, Safety and Tolerability of Intramuscular Injections of Allogeneic PLX-PAD Cells improved recovery following Arthroplasty for Hip Fracture (HF).

Protocol Number: PLX-HF-01 Investigational Treatment: Allogeneic ex-vivo expanded placental stromal cells (PLX-PAD).

STUDY OBJECTIVES
  • To assess the Efficacy, Safety and Tolerability of PLX intra-muscular injections for recovery after arthroplasty for hip fracture

STUDY DESIGN
  • Target enrollment: 240 patients
  • Randomization 1:1
    • 150 million PLX-PAD cells (n=120)
    • Placebo (n=120)
  • Total hip arthroplasty (THA) or Hemiarthroplasty (HA) via lateral surgical approach
  • IP administration IM during surgery in 10 injections (1.5mL each)

STUDY DURATION
  • 52 weeks efficacy follow-up
  • 104 weeks safety follow-up

INCLUSION CRITERIA
  • Male or female subjects between 60 to 90 years of age
  • Subjects suffering low energy trauma with intracapsular neck of femur fracture
  • Planned to be treated with total hip arthroplasty (THA) or hemi arthroplasty (HA), within 48 hours of admission and 72 hours post fracture
  • American Society of Anesthesiologists (ASA) Score ≤ 3
  • Subject able to walk 10 feet/3 meters before the fracture (with or without walking aids and without help of a person most of the time) based on self report

MECHANISTIC SIDE STUDIES/BIOSAMPLING
  • Mode of action in immune biomarkers
  • Mode of action on myoblasts and immune cells

PRIMARY EFFICACY ENDPOINT
  • Short Physical Performance Battery (SPPB) score at week 26


sppb

SECONDARY EFFICACY ENDPOINTS
  • Hip abduction strength of injured leg at Week 26
  • Lower Extremity Measure (LEM)
  • All-cause mortality rate
  • Appendicular Lean Body Mass of injured leg at Week 26 (DEXA)


efficacy_endpoints

HIPGEN PARTNERSHIP

PARTNERSHIP | PARTNERS | CONTACTS | RESERVED AREA

The Network consists of 9 partners from 8 Countries (Germany, Denmark, UK, Ireland, Italy, Switzerland, Israel and United States).
The clinical and research centers in the Consortium have a renowned international expertise on hip fracture arthroplasty and cell therapy respectively while Pluristem is a lead company in the cell therapy development. All the Partners have been selected for their excellence in the field.
The HIPGEN consortium includes also the Irish CRO ICON that will manage the multicentre clinical trial, the company Be the Partner that has developed the platform for patient data management and the service provider company ALTA that will support the consortium in the coordination, dissemination and exploitation, allowing the scientists to focus on the science and the business developer on business. Finally, the International Osteoporosis foundation gives an added value of the consortium by filling the communication gap between science and patients.
The high degree of synergy among our participants ensures that the program will be successful and that their combined output will be greater than the sum of its parts. The European dimension of the project is an added value of the proposal, in terms of achieving the necessary critical mass (regarding patient enrollment, clinical infrastructures, availability of samples for analysis), financial support and good visibility.


consortium



HIPGEN EVENTS

HIPGEN KICK OFF MEETING, 14-16 January 2018
pin Berlin - BCRT Charité


MEETING DOCUMENTS

pdf   Meeting Agenda

pdf   List of Participants


MEETING PHOTOS

HIPGEN DISSEMINATION

PRESS RELEASES

HAIFA, Israel, April 25, 2018 - Pluristem Therapeutics Inc
U.S. Food and Drug Administration (FDA) has cleared Pluristem’s Investigational Drug Application (IND) of its PLX-PAD cell therapy for HIPGEN study

pdf   download the article

 

Dissemination area will also provide:

  • Publications
  • Project flyers
  • Conferences
  • IOF activities