Incyte (INCY) Status Update summary

Clinical data highlights

• INCA033989 demonstrated rapid and robust clinical responses in both essential thrombocythemia (ET) and myelofibrosis (MF), including normalization of platelets, spleen volume reduction, symptom improvement, and significant anemia benefit, especially in relapsed/refractory and JAK inhibitor-naive patients.

• 42% of MF patients achieved SVR25 and 33% achieved SVR35 at week 24; symptom improvement was seen in 93% (monotherapy) and 81% (combination), with 56% achieving anemia response.

• Most patients experienced symptom improvement, with up to 60% achieving ≥50% reduction in total symptom score as best response.

• Combination therapy resulted in 50% achieving ≥25% spleen volume reduction and 86% maintaining stable anemia.

• Responses were observed across CALR mutation types, including Type 1, Type 2, and high-risk co-mutations, with higher doses yielding improved responses in non-Type 1 patients.

Safety and tolerability

• INCA033989 was well tolerated as monotherapy and in combination with ruxolitinib; no dose-limiting toxicities or maximum tolerated dose reached, and over 85% of patients remained on therapy.

• Most adverse events were mild (Grade 1); neutropenia and anemia were the most frequent Grade ≥3 events, with low discontinuation rates due to adverse events.

• No dose-dependent toxicity signals were observed across a wide dose range; side effects were minimal and manageable, with most liver enzyme elevations attributed to underlying disease rather than drug toxicity.

• No evidence of new driver mutations or resistance emerging during therapy; co-occurring high-risk mutations also decreased with treatment.

Molecular and translational findings

• Molecular data showed rapid reductions in mutant CALR clone burden, restoration of wild-type hematopoiesis, and improvements in bone marrow fibrosis, supporting disease-modifying potential.

• Most patients experienced reductions in mutCALR variant allele frequency, with deeper reductions at higher doses and in those with spleen response.

• INCA033989 reduced disease-initiating and -maintaining cells, including CD34+ hematopoietic stem/progenitor cells and megakaryocytes, as shown by single-cell analyses.

• Increased erythroid progenitor cells in bone marrow correlated with hemoglobin increase and clinical anemia response.