4450

Topical Treatment of Skin Toxicities Caused by Biological Anti-Cancer Drugs

Benny Ofra , HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research
Merims Sharon, Hadassah

Application
Many of the antineoplastic molecularly targeted agents, particularly those interfering with signal transduction (e.g., epidermal growth factor receptor inhibitors [EGFRi such as Cetuximab/Erbitux] and small molecule tyrosine kinase inhibitors), are associated with prominent dose-limiting dermatologic complications, including papulopustular rash, xerosis and paronychia. Current strategies for treating skin toxicities caused by EGFR inhibitors are based on the use of systemic antibiotics, topical steroids, moisturizers, and sunscreens, yet these treatments are of limited benefit. Furthermore, the treatments based on systemic antibiotics are recommended even though the pathogenesis of the rash is rarely caused by bacteria. These treatments cause antibiotic resistance (a global public health threat that demand a pressing need in reducing the use of anti-bacterial agents) and impairment of the microbiome and its effect on response to cancer treatment. 

There is an urgent need for a novel and potent treatment for skin toxicities caused by EGFR inhibitors and tyrosine kinase inhibitors. Our novel approach, demonstrating proactive strategy for the management of EGFR therapy-mediated skin rash may help to maximize benefit for oncology patients. Our technology minimizes the negative effects of quality of life and maintains an optimal monoclonal antibody dose at the same time. This leads to a better response rate to anti-cancer treatment.

Clinical Incidence
Papulopustular eruption is the most common cutaneous reaction pattern and is noted in 90% of patients receiving EGFR-targeted monoclonal antibodies. There are an estimated 20,000 patients annually in the US (~15,000 in Europe) for Cetuximab and Panitumumab.

Our innovation
Our innovation combines specific small molecules, topically applied, and delivered via a slow-release system from biodegradable polymeric nanocarriers that penetrate the deep layers of the epidermis which are dense with EGFR.

Technology
A novel specific anti-EGFR inhibitor molecule was identified, synthesized, analyzed, formulated, and tested for functionality in in-vitro and ex-vivo setups:

In-vitro

We developed a screening assay that can highlight potential targets for reducing skin toxicities specific to EGFRi. Over 3,500 small molecules were screened, and three potent lead molecules were identified demonstrating effective reversing of EGFRi-induced skin toxicities.

The lead small molecules could reverse EGFRi-induced keratinocyte damage as seen with functional assays in keratinocyte cell lines and in a full human skin model

Dose toxicity study in rats with our lead molecule did not show a toxic effect   

Ex-Vivo

The nanoparticles penetrate the deep layers of the epidermis as demonstrated in several independent experiments in full human skin.

The Franz Cell chamber assay demonstrated that the lead compounds do not penetrate through human skin.

Competitive advantage

A novel approach for treating skin toxicities caused by EGFRi using new compounds and a unique delivery system targeting the deep layers of the skin.

A potent treatment that will maximize the benefit for oncology patients by minimizing the negative effects of quality of life and maximizing the anti-cancer treatment effects by improving compliance to therapy.

Fast development track as the time to phase I clinical trial is expected to be relatively short due to the topical application aimed for stage IV metastatic oncology patients.

 

 

Contact for more information:

Keren-Or Amar
VP, Business Development, Healthcare
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