Periodic Reporting for period 4 - HIPGEN (Placenta-expanded adherent stromal cells (PLX-PAD) as an innovative therapy for improving recovery and survival following hip fracture arthroplasty – HIPGEN, a multicenter phase III trial)
Reporting period: 2022-01-01 to 2022-09-30
The HIPGEN project aimed at bringing the first regenerative therapy for improving recovery following a surgically treated injury to market approval. The focus of the HIPGEN trial were patients undergoing total or hemiarthroplasty 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 of up to 30% during the first year. The injury itself as well as the consequent surgery presents a huge challenge for elderly patients whose regenerative capacity is low. There is currently no therapy available after hip fracture surgery to address the problem of impaired regeneration, reduced mobility and the risks, including the high mortality. HIPGEN proposes a new innovative therapy to address these issues, which is in an advanced clinical development stage: allogeneic placental cell therapy with placenta-expanded adherent stromal (PLX-PAD) cells for the enhanced recovery following hip fracture surgery.
The initial phase of the project included preparation, submission and finalisation of all study documents. Clinical grade PLX-PAD batches were successfully manufactured, stored and used for the patients’ treatment and sent for accompanying in-depth characterisation to the partners. Consequently, the 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 PLX-PAD cells after arthroplasty has been successfully completed. To meet the negative impact on enrollment and follow-up during the COVID-19 pandemic, home and phone visits were implemented in the study protocols.
In 2021 enrolment has been completed with 240 patients found eligible for randomization into the trial at 21 study sites in Europe, Israel and in the US. After the fulfilment of preparatory tasks analyzing the mechanism of action, samples from study patients are also studied in order to identify surrogate biomarkers for therapy response and to reveal paracrine as well as immune-mediated mechanisms of actions of PLX-PAD on muscle regeneration. 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.
Following the completion of the primary efficacy analysis in July 2022, which showed that the trial did not meet the primary endpoint, the Short Physical Performance Battery, a decision was made to terminate the trial early after patient visit week 52. However, a post hoc analysis could show, that PLX-PAD was an effective accelerator of muscle strength and regeneration. A significant increase in Hip Abduction Strength (HAS) from week 6 was observed at week 26 and week 52 for patients treated with PLX-PAD (n=120), both in the injured leg (p=0.047 p=0.0022) and in the uninjured leg (p=0.073 p=0.0046) compared to placebo (n=120). This new data confirms the results on HAS found in the previously performed phase I/II study. The biomarker analysis revealed, among other results based on a broad portfolio of analyses, trends for a faster recovery of cellular immune parameters, such as HLA-DR on monocytes, and modulation of regeneration, such as in the CD4/CD8 ratio. The in vivo mechanism of action analyses demonstrated pro-regenerative and anti-inflammatory effects of PLX-PAD on human myoblasts from donors and HIPGEN patients.
All patients were followed up until week 52 after treatment, and sites have been requested to follow up patients per telephone who already have been at this visit.
In addition to the scientific progress, the overall awareness of Advanced Therapies in hip fracture patients and of the HIPGEN project itself increased due to diverse dissemination activities by all partners, for example via the HIPGEN website, social media, scientific and public presentations/posters at conferences and workshops as well as the video of the public session of the final meeting in Brussels.
In 2021 enrolment has been completed with 240 patients found eligible for randomization into the trial at 21 study sites in Europe, Israel and in the US. After the fulfilment of preparatory tasks analyzing the mechanism of action, samples from study patients are also studied in order to identify surrogate biomarkers for therapy response and to reveal paracrine as well as immune-mediated mechanisms of actions of PLX-PAD on muscle regeneration. 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.
Following the completion of the primary efficacy analysis in July 2022, which showed that the trial did not meet the primary endpoint, the Short Physical Performance Battery, a decision was made to terminate the trial early after patient visit week 52. However, a post hoc analysis could show, that PLX-PAD was an effective accelerator of muscle strength and regeneration. A significant increase in Hip Abduction Strength (HAS) from week 6 was observed at week 26 and week 52 for patients treated with PLX-PAD (n=120), both in the injured leg (p=0.047 p=0.0022) and in the uninjured leg (p=0.073 p=0.0046) compared to placebo (n=120). This new data confirms the results on HAS found in the previously performed phase I/II study. The biomarker analysis revealed, among other results based on a broad portfolio of analyses, trends for a faster recovery of cellular immune parameters, such as HLA-DR on monocytes, and modulation of regeneration, such as in the CD4/CD8 ratio. The in vivo mechanism of action analyses demonstrated pro-regenerative and anti-inflammatory effects of PLX-PAD on human myoblasts from donors and HIPGEN patients.
All patients were followed up until week 52 after treatment, and sites have been requested to follow up patients per telephone who already have been at this visit.
In addition to the scientific progress, the overall awareness of Advanced Therapies in hip fracture patients and of the HIPGEN project itself increased due to diverse dissemination activities by all partners, for example via the HIPGEN website, social media, scientific and public presentations/posters at conferences and workshops as well as the video of the public session of the final meeting in Brussels.
The HIPGEN project has the potential to advance the clinical application of an “off-the-shelf” cell product for high, unmet medical needs in connection with muscle injury, degeneration and regeneration. Despite the not met primary endpoint of the rather complex SPPB, the potential of PLX-PAD to increase skeletal muscle strength after injury could be further developed in other indications, such as sports injuries, traumatic injuries or iatrogenic muscle trauma. All these indications are frequently seen in the European and international population and constitute a high medical need since no therapies to treat these are currently available. The HIPGEN project can be seen as a blue print of future strategies for clinical development of Advanced Therapy Medicinal Products. Due to the broad spectrum of biomarker and in vitro mechanism of action studies, a vast amount of data will still be analyzed and exploited after the end of the funding period, contributing to a comprehensive in-depth understanding of the immunomodulatory and muscle trophic modes of action of PLX-PAD cells in large and relevant patient cohorts. This can in possible future applications build a string basis for a translation of ATMPs to patients. Consequently, HIPGEN will have significant impact on health services, future research projects in the field and patient management.