The treatment landscape for myelofibrosis, a rare blood cancer, is poised for a potential shift with the emergence of INCA033989, a novel monoclonal antibody targeting the mutated calreticulin (CALR) protein. Preliminary data presented at the American Society of Hematology (ASH) Annual Meeting & Exposition suggest the drug, developed by Incyte, demonstrates promising efficacy and a favorable safety profile, particularly in patients resistant or intolerant to existing therapies like JAK inhibitors.
Currently available treatments for myelofibrosis, including JAK inhibitors, address symptoms but don’t target the underlying genetic drivers of the disease. Approximately 25-30% of patients with primary myelofibrosis and essential thrombocythemia harbor a CALR mutation, making it a significant therapeutic target. INCA033989 distinguishes itself by selectively binding to and internalizing the mutated CALR protein, ultimately leading to the death of cancerous cells while sparing healthy ones. This mechanism, as explained by presenting author Dr. John O. Mascarenhas of the Icahn School of Medicine at Mount Sinai, aims to modify the disease course, a goal not fully achieved by existing treatments.
Phase I Trial Results: Safety and Efficacy
The data presented at ASH stemmed from two ongoing phase I studies – INCA033989-101 (outside the U.S.) and INCA033989-102 (U.S. Only) – evaluating INCA033989 in patients with CALR exon 9-mutated myeloproliferative neoplasms. The analysis focused specifically on myelofibrosis patients who were either ineligible for, resistant to, or intolerant of prior JAK inhibitor therapy, or who had a suboptimal response to ruxolitinib. The studies involved two cohorts: a monotherapy group receiving INCA033989 alone, and a combination therapy group receiving INCA033989 alongside ruxolitinib.
Monotherapy with INCA033989 proved to be “super well tolerated,” according to Dr. Mascarenhas. Nearly all patients (96.2%) experienced some treatment-emergent adverse events, but a substantial majority (86.5%) remained on treatment throughout the study period, a notable achievement for a first-in-human phase I trial. Grade 3 or higher adverse events occurred in 30.8% of patients, with serious events – including abdominal pain with tendonitis, and cases of lymphoma – reported in 9.6% of the cohort. Dose reductions and interruptions were infrequent, at 3.8% and 5.8% respectively.
Efficacy data from the monotherapy cohort showed a spleen volume reduction of 25% or more (SVR25) in 41.7% of patients at week 24, and a 35% or greater reduction (SVR35) in 33.3%. Notably, patients who were treatment-naive to JAK inhibitors demonstrated superior spleen responses (SVR25: 71.4% vs 34.5%; SVR35: 57.1% vs 27.6%) compared to those with prior exposure. A significant 93.3% of evaluable patients reported symptom improvement, with 60.0% achieving a reduction of at least 50% in their Total Symptom Score (TSS50). Improvements in hemoglobin levels were also observed, particularly in anemic patients, with 56.0% achieving an anemia response.
The combination therapy arm, pairing INCA033989 with ruxolitinib, exhibited a similar safety profile. All patients experienced treatment-emergent adverse events, with 65.0% deemed treatment-related. Serious adverse events were reported in 25.0% of patients, including acute myocardial infarction and cases of lymphoma. However, investigators cautioned against overinterpreting the lymphoma cases, noting their occurrence in a patient population already at increased risk.
In the combination therapy cohort, 50.0% of evaluable patients achieved SVR25 at week 24, and 25.0% achieved SVR35. Symptom improvement was reported in 81.3% of patients, with 33.3% achieving TSS50. A substantial 86% of evaluable patients maintained stable anemia during the study, with one patient experiencing a major anemia response.
Disease Modification Potential
Beyond symptom and spleen responses, exploratory analyses suggest INCA033989 may have disease-modifying potential. Immunohistochemistry revealed a reduction in mutated CALR-positive megakaryocytes, accompanied by an increase in their wild-type counterparts. A significant decline in total megakaryocytes was observed, driven by the reduction in mutant CALR-positive cells. Bone marrow fibrosis decreased in 40.0% of patients, and improved erythropoiesis was observed in anemic patients, correlating with anemia responses. A reduction in mutant CALR variant allele frequency was observed in 89.4% of patients with post-baseline measurements, with 10.6% achieving a reduction of at least 25%.
Expert Commentary and Future Outlook
Dr. Prithviraj Bose of The University of Texas MD Anderson Cancer Center, commenting on the data, described the results as “very, very positive” and the drug as “extremely well tolerated.” He emphasized the need for therapies that specifically target the CALR mutation, as current JAK inhibitors do not eradicate the underlying malignant clone. The observed reduction in mutant CALR variant allele frequency suggests a potential for early disease modification.
The investigators concluded that INCA033989 was well-tolerated, with promising spleen and anemia responses and symptom improvements in both monotherapy and combination therapy cohorts. Dr. Mascarenhas stated that the data are “clear and robust,” paving the way for a pivotal registration study in the near future. The development of a subcutaneous formulation is also underway, potentially improving patient convenience.
