Download 1.1 Summary description of project context and objectives

Section 1 - Publishable summary Page 5
1.1 Summary description of project context and 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. By the development and
clinical testing of the here-described novel skin substitutes, we may significantly
contribute to the solution of this problem!
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:
1. Bio-engineering two novel, tissue-like skin grafts, designated denovoDerm and denovoSkin, as well as a
unique dermal (off the shelf) template, termed Novomaix.
2. Applying these novel skin-reconstitution products both in Phase I and multicentrical Phase II clinical trials
3. 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. Establishment and optimization of the GMP-production process of denovoDerm and denovoSkin.
3. Permission to start the clinical trials for all three products from the ethical authorities
4. Permission to start the clinical trials for denovoDerm and denovoSkin from Swissmedic
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.
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1.2 Work performed since the beginning of the project and the main results achieved
so far
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 study protocol for phase II studies is in place. Phase II documents are presently
evaluated by the responsible ethics commission(s).
DenovoDerm and denovoSkin: All SOPs and validations for GMP-production of denovoDerm
and denovoSkin were undertaken. Permission of the responsible ethical commission was
received. Notification from Swissmedic was received. Both denovoDerm and denovoSkin are
now routinely produced under GMP conditions for clinical phase I application. Clinical Phase I
studies were started in May 2014. To date (18.11. 2014) 6 patients were treated in Zurich. First
results are very promising both in terms of safety and clinical outcome. The study protocol for
phase II studies is in place. The phase II documents for denovoDerm and denovoSkin will be
soon evaluated by the responsible ethics commission(s) The Medical Safety Board will soon
come together to evaluate the first denovoSkin and denovoDerm patients. A written report will be
available in 2015.
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.
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
Clinical trial phase 1 for denovoDerm and denovoSkin have commenced in June 2014.

Histological, biochemical and genetic analysis of the products prior and after
transplantation is ongoing.
1.3 The expected final results and their potential impact and use (including the socioeconomic impact and the wider societal implications of the project so far)
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 expect to come up
with a product that 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 up to 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 bioengineered skin graft to be clinically tested elsewhere worldwide. We expect denovoDerm to be
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 supposed to be a smooth and soft 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.
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 envisioned to provide adequate patient care in indications where
split skin thickness grafting alone will result in inferior results (joint surfaces, hands, etc) and
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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 and reliable 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.
The 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. 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 most likely 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.
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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.