SciTech Europa Quarterly speaks to CUTISS’ CEO, Dr Daniela Marino about their plans for the next financing round for automated tissue therapies.
Skin is the largest organ of the human body, composed mainly by an outer epidermis and an inner dermis. It is our interface to the outer world and its total loss is incompatible with life. In contrast to small skin lesion, if large proportions of epidermis and dermis are lost, the resulting full-thickness defects (FTSD) represent a significant, and sometimes unsolvable, problem for surgeons. The classical conditions that often lead to extended full thickness skin loss are burns, avulsion injuries, septic skin necroses, and iatrogenic skin defects.1
Today, FTSD are treated by means of skin autografting: a split-thickness skin graft (STSG) is harvested from a healthy donor site of the patient’s body and transplanted on the full-thickness wound. STSG, being composed of epidermis but only remnants of dermis, are thinner than the wounds, thus, after transplantation, scar tissue is deposited to fill up ‘the gap’ and contraction is promoted to try and reduce the wound volume. Clearly, during the acute phase, donor site shortage represents an unmet need that can be even lethal. In mid-long term, scarring becomes the major issue. Scars are indeed not just disfiguring but also debilitating, highly discomforting, they can be painful and can impair mobility and growth and require corrective surgeries, intense homecare and psychosocial rehabilitation.1
denovoSkin™ a personalised bio-engineering dermo-epidermal skin grafts offers a solution to the lack of permanent skin coverage denovoSkin, the Advanced Therapy Medicinal Product (ATMP) developed at CUTISS, is made of cells isolated from a stamp-sized patient’s split-thickness biopsy and it comprises both an epidermal and a dermal components. Hence, there is no rejection issue after transplantation and the product is safe. Right now, denovoSkin is manufactured with a classical manual procedure where cells are isolated, amplified in 2D and then combined into a skin-like graft using a collagen hydrogel scaffold in 3D. The hydrogel is plastically compressed to ensure mechanical stability and user friendliness (surgeons are used to apply skin on wounds by means of sutures, staples, glues etc.).
However, CUTISS’ Research and Development team is working full speed on scale-up and automation of the manufacturing process supported by an EU H2020 SME Instrument grant, an EU H2020 SME Innovation Associate grant and a Swiss Innosuisse Grant. Two major Swiss engineering companies are involved: Zühlke engineering and CSEM. The ultimate goal is to position denovoSkin as the first-in-class automated-produced tissue therapy that can treat children and adults in a safe, effective and accessible way. The automation program is focusing on three main automated modules: cell isolation, cell expansion and tissue formation. Each module will replace the corresponded manual process. In a second step, the three modules will then be integrated to create an automate production line. The production of skin tissue in the automate has several advantages: among others, robustness, consistency, reproducibility, safety, shorter production time and smaller costs.
The standard of care today follows no specific guidelines when large, deep wounds are to be permanently treated. The healthy skin remaining on the patient body is the only means of real coverage and thus, it is harvested thin (split thickness skin graft, STSG), and meshed, repeatedly. This means that the donor site is also wounded and very often patient suffer sever donor site morbidity. Unfortunately, donor site shortage is a clear unmet clinical need for large and deep skin defects. A few options are available to the surgeons, e.g. reCell®, Keratinocyte Sheets and dermal templates, but all those are applied on meshed STSG. denovoSkin with its permanent, dermo-epidermal structure has the potential to bring in new standards in skin grafting. With the use of denovoSkin surgeons could avoid re-harvesting and meshing of STSG, the healthy donor site could be optimally used, aesthetic outcome would be superior and functionality as well.
Importantly, after the burn acute phase, denovoSkin could then be very beneficial to burn survivors that need or want to correct their scars. Other kinds of elective/reconstructive indications (tumour resections, plastic surgery, etc.) may also benefit from our technology.
The clinical trials status: Phase I safety trial completed
To determine whether this skin substitute could safely provide permanent defect coverage, a phase one clinical trial was performed at the University Children’s Hospital Zurich. Ten pediatric patients with acute or elective deep partial- or full-thickness skin defects were included. Skin grafts of 49 cm2 were bioengineered using autologous keratinocytes and fibroblasts isolated from a patient’s small skin biopsy specimen (4 cm2), incorporated in a collagen hydrogel. Results: graft take, epithelialisation, infection, adverse events, skin quality, and histology were analysed.
Median graft take at 21 days postoperatively was 78% (range, 0 to 100%). Healed skin substitutes were stable and skin quality was nearly normal. There were four cases of hematoma leading to partial graft loss. Histology at three months revealed a well-stratified epidermis and a dermal compartment comparable to native skin. Mean follow-up duration was 15 months. Conclusions: In the first clinical application of this novel skin substitute, safe coverage of skin defects was achieved.2
The clinical trials status: Phase IIb efficacy trials recruiting
denovoSkin has received Orphan Drug Designation for the treatment of Burns by Swissmedic, EMA, an, FDA. It is now in Phase II efficacy trials in Europe (NCT03227146, NCT03229564, NCT03394612). denovoSkin is a safe product and now the success of the efficacy trials is directly dependent on the patient willingness to participate to the study. We are actively recruiting in Switzerland (University Children’s Hospital, www.kispi.uzh.ch/de/Seiten/default.aspx and University Hospital in Zurich, www.en.usz.ch/Pages/default.aspx) and in the Netherlands (VUmc Center in Amsterdam, www.vumc.com and Dutch Burn Centre in Beverwijk, www.rkz.nl/dutchburncentrebeverwijk). We can recruit pediatric and adult patients with acute burns, but also with a need for elective skin grafting (scar reconstruction, tumours, nevi, plastic surgery, etc.). More countries may be added soon (more info on http://cutiss.swiss/clinical-problem-scars/for-patients/). Importantly, Burn Compassionate Patients admitted at European or Swiss Hospitals may also be grafted with denovoSkin.
Financial History and future plans
CUTISS is a spin-off of the University of Zurich (UZH), it was incorporated in March 2017. CUTISS Ltd was awarded with prestigious prizes in Switzerland: The best pitch at the Swiss startup day in 2014, the TOP1 Swiss business plan 2015, the De Vigier prize in 2017, and is TOP1 Swiss biotech 2019 and 2018. Before company incorporation, denovoSkin was developed at the Tissue Biology Research Unit (TBRU), a laboratory associated with the Department of Surgery of the University Children’s Hospital in Zurich, Switzerland, where close collaboration between researchers and surgeons was envisioned to be the ideal substrate to succeed. The message from the clinical team was clear: donor site shortage and scarring have often no solution. The mission for the scientists was also clear: creating a real, innovative and, effective alternative to autografting.
After completion of the Safety Phase I trials funded by the FP7 EU program in October 2016, the startup incubator Wyss Zurich (http://www.wysszurich.uzh.ch/projects/wyss-zurich-projects/denovoskin/) decided to financially support the Phase II trials for denovoSkin. In July 2017, soon after incorporation, the newly funded UZH Life Science Fund, a joint venture of UZH Foundation and Novartis Venture Fund, injected a seed round of one million CHF to launch the automation of production of denovoSkin.
In May 2018, CUTISS Ltd, with a team of sic people, closed a Series A financing round with CHF 7.255 million (lead investor, Giammaria Giuliani, from Giuliani Pharma) and received grants for €4m. As of Today, CUTISS’ team is composed of around 20 people involved in R&D, Automation, Production, and Clinical Trials – a very strong, experienced team that works in close relation with clinical, regulatory and engineering partners. CUTISS has its own R&D labs and is building its own GMP facility to scale up manufacturing at the Biotechnopark in Zurich-Schlieren. A Series B financing round of approx. CHF 30 million) is planned to open in 2019 to support all activities of CUTISS up to the expected market entry of denovoSkin in 2022. These activities will include mainly manufacturing scale up for sales and automation.
Dr Daniela Marino
+41 76 230 8046
Please note, this article will appear in issue 33 of Scitech Europa Quarterly, which is available in December 2019.