Protagonist Therapeutics (PTGX) Study Update summary

Overview of polycythemia vera (PV) and unmet need

• PV is a chronic myeloproliferative neoplasm characterized by overproduction of red blood cells, leading to increased risk of thrombosis, shortened survival, and significant symptoms such as fatigue and cognitive impairment.

• Consistent hematocrit (Hct) control below 45% is critical to reduce cardiovascular and thrombotic risks, but real-world data show 78% of patients have uncontrolled Hct.

• Standard treatments include phlebotomy, low-dose aspirin, hydroxyurea, interferons, and ruxolitinib, but these often result in iron deficiency, suboptimal Hct control, and significant side effects, with most patients eventually requiring cytoreduction.

• Phlebotomy is inconvenient, causes iron deficiency, and is associated with poor long-term adherence and quality of life.

• There is no RBC-specific pharmaceutical option currently available, highlighting a significant unmet need for therapies that provide rapid, sustained Hct control and improve patient quality of life.

Rusfertide mechanism, clinical development, and efficacy

• Rusfertide is a hepcidin mimetic that restricts iron availability to the bone marrow, reducing red blood cell production and controlling hematocrit.

• Phase II PACIFIC study showed rapid Hct reduction to below 45% in a median of 4.9–5 weeks, with 85% of patients achieving target within eight weeks and no need for therapeutic phlebotomy during treatment.

• The REVIVE phase II study enrolled phlebotomy-requiring PV patients, demonstrating 69–69.2% response (not phlebotomy eligible) on rusfertide versus 14.8–15% on placebo in the randomized withdrawal phase.

• Rusfertide improved symptoms in patients with moderate/severe baseline symptoms, including fatigue, early satiety, night sweats, and pruritus.

• Long-term extension data indicate durable Hct control, normalization of iron stores, and sustained symptom improvement, with 80% of eligible patients rolling over to the THRIVE extension study.

Safety profile

• Safety profile is favorable, with most common adverse events being mild injection site reactions; skin malignancies are monitored but not clearly linked to rusfertide.

• Long-term safety data show no grade 4/5 treatment-emergent adverse events, low discontinuation rates, and favorable comparison to historical thrombotic event rates.

• Open-label extension (THRIVE) allows up to 5.8 years of rusfertide therapy, with ongoing safety and efficacy monitoring.