Developing a broad pipeline of precision dermatology products

Targeted cancer therapies have produced significant treatment advances for patients diagnosed with a variety of tumor types, but they are also associated with unique dermatologic toxicities that may hamper treatment efforts and cause significant physical and psychological discomfort for patients. One such class of targeted cancer therapy includes EGFR inhibitors (EGFRi agents). In the skin, EGFR regulates multiple functions including proliferation, adhesion and migration, survival, and differentiation. Consequently, EGFR inhibition in the skin results in adverse skin reactions, which make it difficult for patients to stay on these effective therapies. The papulopustular rash is the earliest and most common dermatologic adverse event of EGFRi treatment, often occurring in 50-80% of patients. In many cases, the rash leads to severe quality of life issues and can even lead to the interruption or cessation of the EGFRi treatment.

The current standard of care for rash treatment in patients undergoing EGFRi typically includes skin moisturizers, topical steroids, and doxycycline that are administered prophylactically from the start of EGFRi therapy and are continued throughout the entire treatment period. If the rash continues to advance, oral steroids and/or antibiotics are administered. However, there are known systemic adverse events associated with these adjunctive therapies, and we believe that physicians and patients try to limit their use, particularly with oral antibiotics. Given the high incidence rate of rash that continues with these patients, as well as the concerns related to potential impacts of antibiotics on these therapies, we believe there is a clear unmet medical need for additional safe and effective adjunctive therapies for addressing papulopustular skin rash.

Additionally, recent studies have suggested that Interleukin-36 gamma, or IL-36g and S. aureus are linked to and play a significant role in the rashes experienced by patients treated with EGFRi’s. IL-36g, is elevated in the skin of patients undergoing EGFRi therapy. IL-36g expression is induced by EGFR inhibition, and Cutibacterium acnes synergistically induces IL-36g in the skin and subsequently IL-8 and NF-kB, which leads to cutaneous neutrophilia. Additional studies have shown that S. aureus is elevated in patients undergoing EGFRi therapy. Mechanistically, EGFRi therapy impairs host defense: impaired expression of antimicrobial peptides, especially against S. aureus; and lowered expression of tight junctions.

ATR-04 is our formulated, drug product candidate for the treatment of EGFRi associated rash. It includes a novel auxotrophic strain of S. epidermidis strain that was selected from our microbial strain library, based on desired properties of IL-36g reduction and inhibition of S. aureus and its biofilms. The current lead strain is called SE484. We then genetically engineered SE484 to be auxotrophic tor D-alanine and to create our drug product candidate, ATR-04. SE484 was chosen from our microbial library based on key characteristics such as inhibition of IL-36g as well as its effect against S. aureus. Together, we expect these mechanisms of action to lead to significant reductions in rash severity among patients undergoing EGFRi therapy.

We believe that ATR-04 has the potential to address current limitations to treatment of EGFRi-associated rash:

• Reduced antibiotic use. From our surveys of clinicians and key opinion leaders, practitioners are reluctant to prescribe systemic antibiotics to patients undergoing EGFRi therapy. We believe ATR-04 would reduce the need for antibiotics in these patients and lead to fewer adverse events due to EGFRi and antibiotic use.
• Better EGFRi compliance. Up to 20% of patients undergoing EGFRi therapy discontinue due to adverse events, primarily due to rashes. We believe we can reduce discontinuation rate in patients undergoing EGFRi therapy and thus increase compliance.
• Better quality of life. Many patients on EGFRi therapy report a poor quality of life due to adverse events and papulopustular rashes. Current treatment options fail to adequately reduce these adverse events. We believe ATR-04 therapy in patients undergoing EGFRi therapy will have reduced rash severity and thus a higher quality of life.

Ichthyosis vulgaris (IV) is a chronic, xerotic, scaly skin disease with an estimated incidence and prevalence of 1 in 250, which gives a total patient population of 1.3 million in the United States. Clinical features of IV usually appear at around 2 months of age and include generalized xerosis and fine, white to gray scales that are prominent on the abdomen, chest, and extensor surfaces of the extremities.

Ichthyosis vulgaris is an autosomal semidominant disease caused by loss-of-function mutations in the gene encoding filaggrin. Filaggrin is an essential structural protein that is derived from profilaggrin, which breaks down into individual filaggrin units in the stratum corneum. These reinforce the skin barrier by binding to keratins and other intermediate filament proteins in the keratinocyte cytoskeleton. Many studies have identified loss-of-function mutations in FLG in IV patients, and these mutations are associated with disorganized keratin filaments, skin barrier defects and microfractures in the stratum corneum leading to enhanced percutaneous allergen sensitization. Moreover, filaggrin and its breakdown products have significant additional functions in the skin including moisturizing the skin (via hygroscopic amino acids or “natural moisturizing factors”), effecting production of antimicrobial molecules (particularly against S. aureus) and maintaining both a beneficial lipid profile and pH in the skin. There are few effective therapies for the treatment of IV.

ATR-01 is our drug product candidate intended to treat ichthyosis vulgaris. We are developing ATR01 as a novel treatment modality for IV that directly addresses the disease pathophysiology. ATR-01 consists of FLG5-6 functional unit of the human FLG protein with an attached cell penetrating peptide. The goal is to supplement the skin with stable delivery of hFLG via topical application and deeper skin penetration with a cell penetrating peptide.