Clinical Programs: Immunology and Hematology
The immune system is poised between protection and destruction. Certain proteins and cells act in messaging networks to regulate the normal immune response. When these networks are disrupted, harmful inflammation can ensue, and this dysfunction plays a central role—often the primary role—in conditions as diverse as allergy, autoimmune disease, and cancer.
White blood cells are important elements in this system. Among them, a cell type of myeloid lineage known as the eosinophil is increasingly recognized as a pivotal player. Eosinophils have multiple roles, including the innate response to parasitic infection, modulation of adaptive immune responses, and maintenance of tissue homeostasis. Under a variety of conditions, eosinophils migrate across endothelial tissues and infiltrate target organs, secreting inflammatory proteins that may cause serious, potentially irreversible, tissue damage.
Asthma is one of the most common chronic diseases in the world, and its prevalence is increasing, particularly in affluent urban populations. In the U.S., about 26 million people, including seven million children, have asthma, creating an annual economic burden estimated to total $56 billion. This annual cost includes 4,000 deaths, approximately two million emergency room visits, 10 million physician office visits, 14 million lost school days, and 15 million lost work days.
Elevated levels of eosinophils are present in one-half of all asthma patients. The recent approval of eosinophil-lowering drugs for asthma has demonstrated that this approach reduces asthma exacerbations. These new drugs are monoclonal antibodies that must be injected or infused in regular clinic visits. Knopp is advancing dexpramipexole, by contrast, as an eosinophil lowering oral agent for asthma.
Across the many other conditions associated with elevated eosinophils, among the most lethal are those grouped under the umbrella classification of hypereosinophilic syndromes (HES). HES is an often fatal syndrome in which eosinophils migrate into specific tissues, often for unknown reasons, damaging organs through the release of toxic proteins and signaling molecules. Among susceptible organs, the heart is most frequently affected in HES, leading to ventricular damage and eventual cardiac failure. Other target organs frequently include the skin, nervous system, lungs, gastrointestinal tract, liver, spleen, and eyes. Even in the face of aggressive treatment, many patients die of HES.
The current standard of care in treating HES relies on the chronic administration of corticosteroids, such as prednisone. While often initially effective at lowering eosinophils and promoting their clearance from tissues, steroids present significant side effects with chronic use, including hormone suppression, elevated blood sugar, loss of bone density, and mood and behavior disturbances.
Moreover, approximately one-third of HES patients fail to respond to steroid administration. In these cases, treatment generally resorts to cytotoxic and chemotherapeutic agents. While at times effective as second-line agents, these drugs are not approved to treat HES, are associated with serious toxicities, and generally are poorly tolerated at doses sufficient to induce remission. Beyond drug treatment, heart valve replacement or removal of the spleen may be required because of the effect of invasive eosinophils in target organs.
As noted by a group of industry and academic authors writing in the Journal of Allergy and Clinical Immunology, "[A]ddtional agents with increased efficacy and decreased toxicity are sorely needed."
Knopp's pipeline consists of investigational drug products that have not been approved by the U.S. Food and Drug Administration. These investigational drug products are still undergoing clinical study to verify their safety and effectiveness.