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Personalized Tissue-Engineered Veins as the first Cure for Patients with Chronic Venous Insufficiency

Periodic Reporting for period 2 - P-TEV (Personalized Tissue-Engineered Veins as the first Cure for Patients with Chronic Venous Insufficiency)

Reporting period: 2018-09-01 to 2019-08-31

VERIGRAFT's technology produces personalised blood vessel transplants. In short, a donated tissue is decellularised, removing donor cells and DNA. The resulting acellular extracellular matrix scaffold is subsequently reconditioned and recellularised with a small sample of peripheral blood from the patient. This unique technology thereby turns an allogeneic (“foreign”) tissue into an autologous (“personalised”) one, avoiding the complications of transplant rejection by the patients´ immune system.
The decellularisation and reconditioning/recellularisation process for blood vessels is protected by strong patents and trade secrets and has been optimised and industrialised at VERIGRAFT. The process has been successfully utilized in vitro to engineer donated cadaveric human vein segments containing valves, and structural integrity and valve function was confirmed. Such personalised tissue engineered veins (P-TEV) have been implanted into the vena cava of eight pigs with no immunosuppression. After five weeks the grafts were exposed and explanted. No rejection, infection, thrombosis or mechanical failure was observed.
VERIGRAFT's P-TEV product will initially be focused on severe chronic venous insufficiency (CVI), where there is a large unmet medical need. The clinical trial program for the treatment of CVI will be initiated in Europe upon Clinical Trial Authorization acceptance in 2018. Limited marketing authorization in a single EU country (e.g. Lithuania, Spain, Switzerland) for P-TEV is expected two years later with subsequent expansion to additional markets (e.g. all of Europe, the US, China, Japan).
CVI is an incurable condition that occurs when the one-way valves in the deep veins of the legs that normally keep blood moving towards the heart do not work effectively. This malfunction causes blood to pool in the lower extremities, resulting in painful swelling and skin ulceration. The most severe stages of CVI affect at least 1.5 million patients in Europe and North America with about 300,000 new cases per year. Today, these patients are treated symptomatically with compression stockings and superficial surgery, and there are no competitive fully-biological CVI cures in development. At an anticipated market penetration of 10-15%, a P-TEV product would benefit between 150K and 225K patients annually. This is a market of at least Euro 2B. The market for VERIGRAFT's personalized tissue-engineered products will be expanded eventually to address additional vascular indications, such as arterial disease.
VERIGRAFT will generate revenues from i) the manufacturing and distribution of ready to transplant P-TEV products in Europe and USA and ii) the sale of reagents and IP rights to licensees in the rest of the world. Commercial distribution of P-TEV is expected to begin by 2020.

This project will commercialise P-TEV - a unique personalised tissue engineered vein for the treatment of patients with severe Chronic Venous Insufficiency (CVI).
CVI is a progressive medical condition in which the valves of the deep veins of the leg are not functioning properly.
The most severe stage is CVI with leg ulceration. No effective treatment is available and a large number of patients would directly benefit from venous vascular surgery.
These patients cannot be cured today because no suitable grafts for replacement of the dysfunctional venous valves have yet been developed.
There are no synthetic products which could replace the function of the bicuspid valves found in the leg veins and the risks associated with allotransplantation are too high.
VeriGraft's technology is the first one positioned to break this paradigm and fill the existing market gap.
The technology allows the personalisation of blood vessels. In short, a donated tissue is decellularised, removing all immunogenic donor cells and DNA.
This results in a clean extracellular matrix scaffold with intact 3D structural properties.
Subsequently, this scaffold is reconditioned/recellularised using a small sample of peripheral blood.
This unique technology turns an allogeneic (“foreign”) tissue into an autologous (“personalised”) one and thus avoids transplant rejection without the need for immunosuppression.
Preclinical development of P-TEV for the treatment of CVI has been completed. The Clinical Trial Dossier is expected to be finalised in Q2 2018. The clinical study protocol has received first ethical board review approvals in two European countries. Clinical-grade manufacturing processes have been established, and production of P-TEV is currently being transferred to outsourced facilities in Spain and Lithuania. The preclinical data as well as the large animal safety studies performed in pigs, will form the basis of the Clinical Trial Application dossier along with the ethical board review approval and a manufacturing license at the production facility. A similar process is being pursued on a country to country basis in the selected countries.
A phase I/II clinical trial to evaluate safety and efficacy is planned to start upon CTA acceptance. The study protocol has been finalised and has received national ethical review board approvals. The study will be conducted in collaboration with vascular surgeons with extensive experience in vein surgery. This first trial will include 12-15 patients with severe CVI due to dysfunctional valves in the upper leg vein. Patients will receive a single P-TEV transplant containing a functioning valve to replace the incompetent valve in the groin region. Patients will be followed for twelve months to demonstrate safety and show initial measures of treatment efficacy.
The clinical proof-of-concept for P-TEV for treatment of CVI is to be established in this SME Instrument programme. The project will include a first-of-its-kind clinical study and GMP process development, that will grant VERIGRAFT market access by 2020 and serve as a stepping stone to marketing approval by the European Medicines Agency. The EU-added value of the project is unparalleled, as it constitutes a breakthrough in one of future medicine's most promising fields – advanced personalised regenerative medicine, bringing significant long-term budgetary relief to Healthcare systems. Most importantly, the P-TEV project will pave way for treatment of CVI, a hitherto uncured disease that affects millions of inhabitants and decrease quality of life significantly for the patients.