Community Research and Development Information Service - CORDIS

FP7

EuroSkinGraft Report Summary

Project reference: 279024
Funded under: FP7-HEALTH

Periodic Report Summary 3 - EUROSKINGRAFT (A novel generation of skin substitutes to clinically treat a broad spectrum of severe skin defects)

Project Context and Objectives:
Overview: Scientific, clinical and commercial objectives

PROJECT CONTEXT
Large full thickness skin defects resulting from burns, congenital giant nevi, disfiguring scars, soft tissue trauma, tumour resection and disease leading to skin necrosis, represent a significant and common clinical problem worldwide. This problem is far from being solved!
The main challenge encountered is that most autologous skin grafting techniques are based on transplanting split thickness skin (today’s gold standard). Split thickness skin contains all of the epidermis, but only remnants of the dermis. This lack of dermal tissue frequently leads to significant scarring, hence to unsatisfying functional and cosmetic results. Our concept to overcome this problem is derived from our long standing collaboration between scientists and clinicians. This resulted in the insight that improving the quality of the reconstituted dermis is of paramount importance to significantly ameliorate the clinical outcome. In addition, we are stringently aiming at a one-step surgical procedure (instead of the very common two step procedure that employs acellular templates such as Integra Artificial Skin®).

OBJECTIVES
There are three basic objectives of this project:
-Developing two novel, tissue-like skin substitution products, designated denovoDerm and denovoSkin, as well as a unique dermal (off the shelf) template, termed NovoMaix.
-Applying these novel skin-reconstitution products both in Phase I and multicentrical Phase II clinical trials
-If successfully tested on patients, founding a company and bringing denovoDerm and denovoSkin to the European and international markets.

Specific scientific, technical, regulatory and clinical objectives
1. Production and CE certification of NovoMaix and characterization of all cell-free matrix materials used during the clinical trials.
2. Development and production of 5 medical grade collagen compressing devices and of 5 different types of disposable cell-culture devices
3. Establishment and optimization of the GMP-production process of denovoDerm and denovoSkin.
4. Permission to start the clinical trials for all three products from the authorities
5. Production of denovoDerm and denovoSkin under GMP-conditions for Phase 1 and Phase 2 clinical trials.
6. Phase I clinical trials using NovoMaix and denovoDerm/denovoSkin
7. Phase II clinical trials using NovoMaix and denovoDerm/denovoSkin
8. Histological, biochemical and genetic analyses of the skin substitutes prior and after their transplantation

Project Results:
Novomaix: Novomaix has received CE certification in March 2013. Subsequently, Novomaix was first produced for the Phase I study in small product sizes and since the recently performed scale-up by Matricel it can now also be produced routinely in larger product sizes. The clinical Phase I studies in VUMC and UKB are completed. 16 patients were treated. Novomaix is proven to be safe when used on human patients. All required documentation and data management was performed. The Phase II trials have started, 9 patients have been treated at the VUMC.
denovoDerm and denovoSkin: Five identical compression devices were produced and delivered by MDC. Five different types of disposable cell-culture devices were produced to support the appropriate culturing and transport of the types of bio-engineered skin grafts. All SOPs and validations for GMP-production of denovoDerm and denovoSkin were undertaken. Permission of the responsible ethical commission and Swissmedic was received. Both denovoDerm and denovoSkin are now routinely produced under GMP conditions for clinical application. Clinical Phase I pediatric studies were started in May 2014. To date 10/10 patients were treated with denovoSkin, 2/10 patients were treated with denovoDerm. A total of 12 patients were treated in Zurich. First results are very promising both in terms of safety and clinical outcome. The Phase I denovoDerm is recruiting. The denovoSkin Phase I is complete. The study protocol phase II and the necessary documentation for the initiation of the multi-centric Phase II trials are finalized and are ready to be submitted to both the Swiss and the Dutch authorities.
The main results achieved so far are:
• Approvals for Phase I Clinical Trials were given in all centers for all products
• Personnel involved in the clinical studies have received trainings in Good Clinical Practice (GCP).
• All relevant forms (SOPs and WIs) according to GCP are available at the study sites.
• A list of all relevant forms (SOPs and WIs) of internal study specific processes is established. SOPs and WIs have been finalized and distributed.
• A Trial Master File containing all relevant forms to document everything according to GCP is established and available at the study sites.
• A detailed monitoring plan was established by the CTC and has been executed
• The database system is done and the database is operational.
• eCRFs for the denovoDerm/denovoSkin and Novomaix phase-I-studies are ready.
• Novomaix has received CE certification and safety analysis was completed.
• The device for the plastic compression of collagen type I hydrogels under GMP conditions has been designed, produced, and tested. In addition its packaging and sterilization were established. Five compression devices are now available for the TBRU to produce denovoSkin and denovoDerm.
• In parallel to the production of the compression device, six accessory, disposable devices were designed, produced, extensively tested, packaged and sterilized. Some of these devices are compression-associated; others are cell culture-associated.
• Phase I trial for Novomaix is complete, phase II trials have started.
• Phase I trial for denovoSkin is complete, phase II documents are ready to be submitted to the authorities.
• Phase I trial for denovoDerm is in recruitment phase.
• Histological, biochemical and genetic analysis of the products prior and after transplantation is ongoing and close to completion.
• A new heatable transport box was developed in collaboration with the company “SkyCell” in Switzerland to allow shipping of both skin biopsies and bio-engineered skin grafts.
• An audit by Swissmedic evaluating our GCP standards and procedures was successfully passed

Major recent achievements
• The business plan for the startup CUTISS was prepared and received the Swiss Venture Award for the best business plan in 2015
• The Orphan Drug Designation (ODD) both by the EMA and Swissmedic were reached for denovoSkin to be applied on burn patients
• A follow-up project of the EuroSkin Graft project was positively evaluated by the newly etablished Wyss Translational Center Zurich , hence a sub team of the TBRU received a membership in this very prestigious Center. Therefore, clinical trials will be continued after the FP7 funding, and CUTISS can be spun off the University of Zurich and continue its business development within the Wyss Center.
• - in terms of dissemination the work of the TBRU and clinical work of the Swiss burn center were mentioned at several occasions in Swiss TV and in the newspapers
• - explanatory videos about the different scientific parts of EuroSkinGraft were prepared at our last GA. They can be found on the youtube channel of GABO:mi and are publically accessible. They are also embedded on our website under: http://www.euroskingraft.eu/index.php?id=1118

Potential Impact:
The expectations of the consortium were initially based on our data of basic and pre-clinical research and on the data and experiences of other scientist and clinicians. Hence, what we expected from the clinical application of the three products Novomaix, denovoDerm and denovoSkin was based on previous knowledge and intellectual anticipation. As Phase I studies were, and still are, performed we are now in the position to base our expectations (in terms of final results) on first clinical data.
Novomaix is an acellular “off the shelf” dermal template that is to be clinically applied in combination with split thickness skin in one single surgical intervention. We have first indications that Novomaix improves the pliability and texture of the transplanted split thickness skin graft in comparison to split thickness skin grafting alone. As an acellular medical device Novomaix will of course be less expensive when compared to the bio-engineered skin grafts denovoDerm and denovoSkin (which are ATMPs). As an off the shelf product, it can be stored for upto 3 years and its distribution can be easily performed without sophisticated storage requirements during transportation.
DenovoDerm is an autologous dermal substitute that is to be used in combination with split thickness skin in one surgical intervention. Presently we do not see a comparable bio-engineered skin graft to be clinically tested elsewhere worldwide. denovoDerm canbe transplanted onto the patient after a preparation time of about 15 to 20 days. The result is thought to be a smooth and soft, pigmented skin that grows with the paediatric patient. Of course it will also be used on adult patients. We expect excellent functional and cosmetic results both in acute and elective cases.
DenovoSkin is our high end autologous dermo-epidermal skin graft that can be handled by the surgeon in a convenient and easy way in one surgical intervention. Presently we do not see a comparable bio-engineered skin graft to be clinically applied elsewhere worldwide. Its preparation takes about 20 to 28 days and requires a relatively small biopsy. Apart from the biopsy no split thickness skin is needed. The result is a smooth and soft skin that grows with the paediatric patient. Of course it will also be used on adult patients. First Phase I data suggest excellent functional and cosmetic results both in acute and elective cases

Therapeutic impact
• In contrast to the presently most common, clinically applied, acellular dermal template Integra Artificial Skin, the application of which requires two operations (a second operation three weeks after the first one) all three skin substitution products (Novomaix, denovoDerm and denovoSkin) are applied in only one surgical intervention. This means a significantly reduced burden to patients, their relatives, health insurances, and certainly a reduced workload for the teams performing these operations.
• NovoMaix, has high potential as an off the shelf product to be applied in one-step skin reconstitutions. Novomaix is expectedto provide adequate patient care in indications where split skin thickness grafting alone will result in inferior results (joint surfaces, hands, etc) and where there is no option to treat the patient with a bio-engineered skin graft due to e.g. local non-availability of the treatment, or costs for the treatment.
• Likewise, both cellular skin substitutes, denovoDerm and denovoSkin, will be applied in one surgical intervention. These substitutes exhibit the structure and function of skin immediately after their transplantation. The dermis-like properties of denovoDerm instantly and significantly support the overlying split thickness skin. The dermo-epidermal substitute denovoSkin unites many properties of autologous full thickness skin. The medical impact here is the rapid take of these substitutes, and their rapid transition into functional human skin. First clinical studies suggest that scarring and shrinking are minimal with both products. The long-term pliability, hence the overall quality, of the reconstituted skin is expected to be excellent. Using denovoSkin, no split-thickness skin donor sites will be created, which means that significant surgical trauma including all eventually associated morbidity is avoided. Generally and most importantly, the quality of life of a large group of patients is supposed to be significantly improved.
• Of note is that in particular denovoSkin may be an excellent skin substitute to be used to treat chronic wounds (ulcera). In addition, the keratinocytes in denovoSkin may be combined in a distinct ratio with autologous melanocytes to treat certain forms of Vitiligo, in which skin pigment has disappeared due to an autoimmune process.
Socio-Economic impact
• Potential users of the three novel products are burn surgeons, plastic reconstructive, and aesthetic surgeons and dermatologists. Clinical application of these novel products is expected to significantly reduce a common and central clinical problem.
• All three skin substitution products (Novomaix, denovoDerm and denovoSkin) are to be applied in only one surgical intervention. Already this means a significant reduction of the economic burden.
• We expect our skin substitutes to grow to the same degree as the body of a child grows. First results on denovoSkin confirm our expectations. Thus, the problems we presently have in particular at the joints of growing children may not occur. Also this is anticipated to significantly reduce secondary surgical interventions and therefore costs.
• Patents on the skin substitutes as well as on the hydrogel compression device are already filed. The hydrogel compression device will contain disposable elements. Also these will be patented and separately distributed and sold on the European, perhaps world market.
• Commercial marketing of devices, matrix templates and skin substitutes is envisaged, and to be supported by the published results of the clinical trial program and by the involved surgeons.
• A costing program is presently run in parallel with the clinical evaluation of the devices, matrix templates and skin substitutes, to obtain commercial quotations for the manufacture of these products in actual market volumes. The results of this costing program will therefore be available at the same time as the results of the clinical evaluation, and will enable potential investors to quantify the investment needed to found a start-up company and to commercially exploit these products.
• Volume sales for denovoDerm and denovoSkin will occur via a new company (CUTISS) being established to commercially exploit the various products through a conventional manufacturing & sales business model.
• The business plan for the startup CUTISS was prepared and received the Swiss Venture Award for the best business plan in 2015
• The Orphan Drug Designation (ODD) both by the EMA and Swissmedic were reached for denovoSkin to be applied on burn patients

List of Websites:
www.euroskingraft.eu

Related information

Contact

Reichmann, Ernst (Head of Tissue Biology Research Unit)
Tel.: +41 44 63 489 11
Fax: +41 44 634 89 18
E-mail

Subjects

Life Sciences
Record Number: 188083 / Last updated on: 2016-08-24