Rusfertide (PTG-300)

Rusfertide (PTG-300) is a novel injectable synthetic mimetic of the natural hormone hepcidin that offers greater potency, solubility, and stability, which translates to better in vivo PK and PD characteristics and manufacturability in comparison to the natural hormone. Hepcidin is a key regulator of iron absorption, storage, and distribution in the body and thereby controls the production of red blood cells (RBC) and abnormal tissue storage of iron. Rusfertide is currently in an ongoing Phase 2 study in patients for the treatment of polycythemia vera (PV).

We believe that rusfertide has the potential to provide substantial benefit to patients with erythrocytosis or abnormal tissue iron overload by managing hematocrit in a rapid, sustained and durable manner thereby dramatically decreasing the need for therapeutic phlebotomy. Our ongoing clinical studies suggest that Rusfertide has a unique iron regulatory mechanism which allows for persistent control of hematocrit without causing iron deficiency. Rusfertide controls iron metabolism by 1) preventing iron absorption in the small intestine and 2) redistributing iron from the blood to the macrophage storage sites in certain organs and tissues that leads to a restoration of an appropriate iron balance throughout the body. Specifically in PV, rusfertide appears to control RBC production by regulating the amount of iron available to the bone marrow for hemoglobin and RBC synthesis.

Polycythemia Vera (PV) Overview

PV is a rare myeloproliferative neoplasm characterized primarily by the overproduction of RBCs. The main underlying cause of PV is a mutation in the Janus Kinase 2 (JAK2). PV is a serious chronic condition of increased RBC count and iron deficiency, which causes the blood to thicken with RBC shape deformity putting patients at higher risk of cardiovascular and thrombotic events such as heart attack and stroke, along with important Qualify of Life symptoms. Patients are typically stratified as low or high risk based on age and medical history. 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% in order to reduce the risk of further cardiovascular or thrombotic events. PV is a slow progressive disease with a median survival horizon of 20 years. PV may ultimately progress to myelofibrosis or leukemia.

PV affects approximately 160,000 patients in the U.S., with a similar prevalence in Europe, representing an estimated market opportunity of approximately $1.0 billion to $2.0 billion. Patients are typically diagnosed between the ages of 50 and 70. 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 the analysis of the large data claims database, current therapies do not offer adequate hematocrit control below 45% as recommended in the NCCN 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.

Hereditary Hemachromatosis (HH)

Hereditary hemochromatosis (HH) is a genetic disorder characterized by excessive iron absorption due to a deficiency or dysregulation in hepcidin. The disorder results in the accumulation of excess iron in the body’s organs. Approximately one million people in the United States have HFE mutations consistent with type 1 HH; out of these, 10 to 15 percent develop clinical manifestations of the disease. The clinical symptoms of hemochromatosis usually appear after significant iron accumulation—generally after the age of 40. Early signs are nonspecific and can include weakness, lethargy, fatigue, arthropathy/joint pains, increased skin pigmentation, hair loss, impotence, vertigo, and loss of memory.

In HH types 1-3, mutations in genes encoding hepcidin regulators or hepcidin itself lead to diminished production of hepcidin, thus decreasing the inhibitory effect of hepcidin on duodenal iron absorption and causing clinical iron overload. Hepcidin deficiency leads to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may be a significant driver of oxidative stress contributing to the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also, complaints such as asthenia and disabling arthritis.

The goal of treatment in HH patients is to reduce the development of such complications. Per ACG Guidelines, patients with elevated serum ferritin above 200 ng/mL in females and 300 ng/mL in males along with a transferrin saturation (TSAT) at or above 45 percent will require treatment to reduce serum ferritin to the range of 50-100 ng/mL and subsequently decrease TSAT levels to below 45 percent.

There is no approved medicine for treatment of HH, and phlebotomy continues to be the main treatment option. Patients living with clinical manifestations of HH require continued phlebotomies to de-iron organ systems, for their entire lives to limit end-organ damage especially in the liver. Therapeutic phlebotomy has been generally effective in removing excess iron, maintaining a healthy iron distribution, and preventing most of the complications associated with excess iron in the body, this treatment does not target the biological mechanisms leading to iron metabolism disturbance.There is still an important need to reduce availability of free toxic iron to the tissues. Furthermore, approximately 25% of patients in maintenance felt that receiving phlebotomies was “inconvenient” or “very inconvenient”, and patient compliance with phlebotomies generally declines over time.

In hepcidin-deficient mouse models of hemochromatosis, a mini-hepcidin and rusfertide were found to be effective in preventing and decreasing iron loading in the liver compared to vehicle treated control mice that were iron overloaded. These pre-clinical observations along with our clinical findings in the current study suggest that a hepcidin mimetic such as rusfertide may be effective for preventing iron overload in patients with hemochromatosis.

Rusfertide (PTG-300)

We believe that rusfertide has the potential to provide substantial benefit to patients by providing a therapy focused on managing hematocrit in a rapid, sustained, and durable manner and dramatically decreasing the need for therapeutic phlebotomy alone or in combination with cytoreductive therapies. This has the potential to reduce the risk of thrombotic events. Rusfertide is a non-cytoreductive mimetic of the natural hormone hepcidin, the master regulator of iron metabolic homeostasis in the body. Rusfertide has a unique iron regulatory mechanism which, per early results from our ongoing Phase 2 study in PV, allows for well- controlled hematocrit without causing iron deficiency and its associated quality-of-life symptoms. Rusfertide controls iron metabolism by 1) preventing iron absorption in the small intestine and 2) redistribution of iron from the blood to the macrophage storage sites in certain organs and tissues leading to a restoration of an appropriate iron balance throughout the body. Specifically in PV, rusfertide appears to control RBC production by regulating the amount of iron available to the bone marrow for hemoglobin and RBC synthesis.

Oral Peptides for Inflammatory Bowel Disease (IBD)

PN-943

PN-943 is a potential first-in-class oral, alpha-4-beta-7 (α4β7) integrin-specific antagonist peptide. This product candidate is being developed initially for the potential treatment of moderate-to-severely active ulcerative colitis (UC). α4β7 integrin is considered to be one of the most GI-specific biological targets for inflammatory bowel disease (IBD) due to its binding to MAdCAM-1, an extracellular protein that resides mostly in the GI vasculature. PN-943 peptide is largely restricted to the GI tract as a topical approach to treat inflammatory disease.

Ulcerative Colitis Overview

Ulcerative Colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by chronic inflammation of the colonic mucosa and submucosa. Today, there are an estimated one million patients living with UC in the United States alone. Current treatments range from corticosteroids to immunomodulators. Despite the availability of these treatments, there continues to be a significant need for novel, safe, effective, and convenient treatment options for patients.