Addressing Unmet MEDICAL Needs with Peptide Technology

TREATMENT FOR HEMATOLOGY & BLOOD DISORDERS

Discovered through our peptide technology platform, rusfertide is currently being investigated in a phase 3 clinical study in the setting of polycythemia vera (PV), a rare chronic blood disorder that affects about 150,000 patients in the U.S.

Our ongoing clinical studies suggest that rusfertide has a unique iron regulatory mechanism which allows for persistent control of hematocrit without causing iron deficiency.

TREATMENT FOR INFLAMMATORY & IMMUNOMODULATORY DISORDERS & DISEASES

IL-23 and JNJ-2113

Interleukin 23 (IL-23) is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. The pathologic binding of IL-23 to IL-23 receptor can trigger chronic diseases that are associated with inflammation, including psoriasis and ulcerative colitis. Current approaches for targeting IL-23 include antibodies that need to be injected under the skin or into the body. As of early 2024, there are no oral therapies that target the IL-23 pathway that are approved for use in diseases associated with immunity or inflammation.

JNJ-2113 (formerly known as PN-235), a potential first-in-class targeted oral peptide designed to selectively block the IL-23 receptor, was discovered and is being developed pursuant to a license and collaboration agreement between Protagonist and Johnson & Johnson. In nonclinical studies, JNJ-2113 potently blocked downstream cytokine signaling and had similar efficacy to an IL-23 antibody in imiquimod-induced psoriasis-like mouse models of inflammation.

Protagonist completed a Phase 1 study with JNJ-2113 in October 2021 and Johnson & Johnson retains exclusive, worldwide rights to develop and commercialize compounds derived from the research conducted pursuant to the agreement against a broad range of indications.

Several late-stage clinical studies investigating JNJ-2113 are ongoing, including the phase 2b ANTHEM clinical study that is enrolling patients with ulcerative colitis. In addition, JNJ-2113 is being studied in the ICONIC program, which includes four phase 3 studies that are enrolling patients with moderate-to-severe psoriasis.

Details regarding ANTHEM-UC and the ICONIC Phase 3 psoriasis trials can be found on clinicaltrials.gov.

IL-17 and Oral IL-17 Peptide Antagonists

Similar to IL-23, interleukin 17 (IL-17) is also a naturally occuring cytokine. Molecules that target and bind to IL-17 can inhibit the release of proinflammatory cytokines and chemokines. Release of these biological molecules may help attenuate diseases and disorders that are mediated by IL-17, including skin conditions such as psoriasis, hidradenitis suppurativa (HS), spondyloarthritis, plaque psoriasis, and psoriatic arthritis. As of early 2024, there are no approved oral therapies that target IL-17 for use in patients with these conditions.

Given the successful development of the oral IL-23 receptor antagonist JNJ-2113 (formerly known as PN-235), Protagonist Therapeutics is using its peptide technology platform to develop a potential first-in-class oral IL-17 peptide antagonist against a proven target, IL-17. Protagonist Therapeutics seeks to develop an oral peptide that has similar or better specificity and potency relative to currently available options for IL-17-mediated diseases, and disorders and aims to nominate a lead candidate for clinical research by the end of 2024.

ORAL HEPCIDIN MIMETICS

Based on our clinical success with rusfertide, we have initiated a discovery program to develop oral mimetics of hepcidin for the treatment of erythrocytosis or abnormal tissue iron overload. The goal of this program is to expand our rusfertide franchise by providing greater dosing convenience.

RUSFERTIDE (PTG-300) AS A TREATMENT FOR POLYCYTHEMIA VERA (PV)

PV is a myeloproliferative neoplasm characterized primarily by the overproduction of red blood cells (RBCs) and increases in white blood cells and platelets. The main underlying cause of PV is a mutation in the Janus Kinase 2 (JAK2) gene. In patients with PV, there is an increased incidence of thrombotic and cardiovascular events. Other symptoms also occur, including itching, night sweats, problems with concentration, and fatigue. The age and medical history of a patient will determine whether they have low- or high-risk disease.

Regardless of risk categorization, treatment guidelines for PV are consistent in their recommendation to control the patient’s hematocrit (RBCs as a percentage of whole blood) below 45% to reduce the risk of cardiovascular or thrombotic events. PV is a slow, progressive disease; median survival is approximately 20 years. PV can progress to myelofibrosis or leukemia.

PV affects approximately 150,000 patients in the U.S., with a similar prevalence in Europe, representing an estimated market opportunity of approximately $1-2 billion per year. Patients are typically diagnosed between the ages of 50 and 70. A recent analysis of patient data from a large medical claims database indicates that the current treatment paradigm consists primarily of therapeutic phlebotomy, hydroxyurea, or a combination of hydroxyurea and phlebotomy.

According to an analysis of the large data claims database*, current therapies do not offer adequate hematocrit control below 45% as recommended in current treatment guidelines. In fact, less than 25% of patients in the data set had all hematocrit test results under 45%, indicating that as many as 70,000 patients in the U.S. may be at elevated risk of cardiovascular and thrombotic events.

*Verstovsek S, et al., Real‑world treatments and thrombotic events in polycythemia vera patients in the USA. Ann Hematol 2022;101(1):131-7.

Rusfertide (PTG-300) for Potential Treatment for Hemochromatosis

Hemochromatosis protein (HFE)-related hemochromatosis is an inherited iron overload disorder characterized by excessive absorption of dietary iron due to insufficient hepcidin production. Approximately one million people in the United States have HFE mutations consistent with type 1 hemochromatosis; out of these, 10 to 15 percent develop clinical manifestations of the disease.

In a phase 2 open-label study, the hepcidin mimetic rusfertide prevented iron reaccumulation in the absence of therapeutic phlebotomy, demonstrating the potential utility of using rusfertide in the setting of hemochromatosis. These findings were published in the journal Lancet Gastroenterology and Hepatology*.

*Kowdley KV, et al. Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial. Lancet Gastroenterol Hepatol 2023;8(12):1118-28.