THE CUTTING-EDGE SCIENCE TO TARGET CRUCIAL DRIVERS
OF INFLAMMATION

Our proprietary drug discovery and development engine has identified several immune drivers that have the ability to be “tuned up” or “tuned down” to modulate the immune system, either to suppress an overactive immune response in allergic inflammatory diseases or to initiate an immune response against cancer.

RPT904 is a novel half-life extended monoclonal antibody (mAb) designed to bind free human immunoglobulin E (IgE) a key driver of allergic diseases. We plan to develop RPT904 initially as a treatment for food allergy and chronic spontaneous urticaria (CSU) and potentially other allergic inflammatory diseases in the future. In a first-in-human study in healthy volunteers, RPT904 demonstrated extended pharmacokinetics (PK) and pharmacodynamic (PD) properties compared to the first generation anti-IgE mAb omalizumab (Xolair®). With the extended half life, RPT904 has the potential to be dosed every 8 to 12 weeks, compared to every 2 to 4 weeks for omalizumab. RPT904 also has the potential to treat patients with high IgE or bodyweight who are currently not eligible to be treated with omalizumab.

We have identified the cell surface receptor CCR4 as a drug target that potentially has broad applicability in inflammatory diseases. Th2 cells produce inflammatory cytokines such as IL-13, express high levels of CCR4 and are clinically validated drivers of many inflammatory diseases, including atopic dermatitis (AD), asthma, CSU, chronic rhinosinusitis with nasal polyps (CRSwNP), alopecia areata, prurigo nodularis and eosinophilic esophagitis. We are currently pursuing different novel oral CCR4 antagonists for the long-term treatment of these inflammatory diseases by blocking the migration of inflammatory Th2 cells into inflamed tissues.

While this Th2 response may be highly effective against foreign pathogens, particularly parasites, sometimes the body overreacts to benign substances in this way, resulting in a significant influx of Th2 cells, leading to highly inflammatory conditions. We are currently pursuing different novel oral CCR4 antagonists for the long-term treatment of these inflammatory diseases by blocking the migration of inflammatory Th2 cells into inflamed tissues.

Our drug candidate tivumecirnon (FLX475), targets the important cell surface receptor CCR4 (C-C Motif Chemokine Receptor 4). Chemokines specific to CCR4 are secreted from allergically inflamed tissues and from tumors, but not from healthy tissues. Our proprietary approach is designed to prevent the recruitment of disease-promoting immune cells into inflamed tissues and tumors in order to treat allergic inflammatory diseases and cancer.

1XOLAIR® is a registered trademark of Novartis AG

ANTI-IGE IN INFLAMMATORY DISEASE:
addressing elevated immunoglobulin E (IgE) levels in allergy and immune disorders

Elevated immunoglobulin E (IgE) plays a key role in the allergic inflammatory process, which makes it an ideal drug target for allergic diseases. Anti-IgE therapy has been validated by an approved drug, omalizumab, which has been used to treat a number of allergic conditions for nearly two decades. While a significant medical advance, there is a need for improvements in the potency and dosing schedule for anti-IgE therapy.

IgE in Food Allergy

Food allergy is a significant and growing health problem in the United States, Europe and throughout the developed world. It is estimated that over 17 million people in the United States have been diagnosed with a food allergy, including approximately six million children. Approximately 40% of people with a food allergy are allergic to more than one food and approximately half of food-allergic people in the United States have had a severe reaction from their food allergy.

Food allergy occurs when the immune system responds to a harmless food as if it were a threat. In a non-allergic patient, tolerance for food proteins develops early in life and the immune cells do not mount a response when food proteins are detected. In an allergic patient, the immune system is sensitized to one or more food proteins, or allergens (“sensitization” phase). As a result of this sensitization, the patient’s immune system produces IgE antibodies, which are directed against that particular allergen. The IgE antibodies bind to mast cells and basophils via its receptor called FceR1. When an IgE antibody bound to these immune cells encounters the allergen it is directed against the mast cells and basophils are activated and release histamine and other inflammatory mediators which then provoke the symptoms of an allergic reaction (“effector” phase). Symptoms may include hives, swelling, vomiting, abdominal pain, wheezing, breathlessness and lowered blood pressure. Allergic reactions can be triggered by exposure to minute quantities of the relevant food allergen and can be painful, frightening and potentially deadly. Severe and potentially life-threatening reactions are referred to as anaphylaxis, and such reactions require urgent medical attention and often result in treatment at hospital emergency departments.

CCR4 INHIBITION IN INFLAMMATORY DISEASE:
“Down regulating” the inflammatory response

In inflammatory diseases, chemokines recruit helper T type 2 (Th2) cells to inflamed tissues. Once Th2 cells enter tissues such as the skin or the airways in the lung, they secrete proteins known to drive the inflammatory response.
In atopic dermatitis, there are higher levels of these inflammatory ligands compared with healthy humans and these ligands also correlate with the severity of disease.

CCR4 INHIBITION IN CANCER:
Unlocking antitumor immunity

In cancer, the secretion of certain chemokines from tumor cells and tumor-resident immune cells is responsible for the recruitment of immunosuppressive regulatory T cells (Treg) to tumor sites and represents a dominant pathway for downregulating the immune response.
Blocking the migration of Treg through CCR4 has the potential to restore naturally occurring antitumor immunity as well as to synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators and adoptive T cell therapy.

Zelnecirnon (RPT193)
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Tivumecirnon (FLX475)
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Discovery Programs
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