Constellation Pharmaceuticals, Inc. announced that two oral presentations and three posters relating to the Phase 2 MANIFEST and the Phase 3 MANIFEST-2 clinical trials of CPI-0610 in myelofibrosis (MF) were presented at the American Society of Hematology (ASH) Annual Meeting and Exposition. The preliminary data in these presentations are based on a data cutoff of September 29, 2020, and reflect an analysis of clinical activity in 63 first-line (1L) and 94 second-line (2L) or later patients. Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients: 42 of 63 evaluable patients (67%) achieved a =35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). The median spleen volume reduction was 50%, 34 of 60 evaluable patients (57%) achieved a =50% reduction in Total Symptom Scores (TSS50) at 24 weeks. The median TSS reduction was 59%, Arm 1 (2L or later) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients. 7 of 23 (30%) evaluable patients that were not transfusion dependent at baseline (non-TD) achieved SVR35 at 24 weeks, the primary endpoint for cohort 1B. 10 of 21 (48%) evaluable non-TD patients achieved TSS50 at 24 weeks 10 of 20 (50%) evaluable non-TD patients who did not receive transfusions 12 weeks prior to treatment achieved a =1.5 g/dL increase in hemoglobin 3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. 8 of 21 (38%) evaluable non-TD patients achieved TSS50 at 24 weeks 13 of 36 (36%) evaluable TD patients converted to transfusion independence, the primary endpoint for cohort 2A Translational data In samples from patients in Arm 3, 16 of 48 evaluable patients (33%) had at least one grade improvement in bone marrow fibrosis and in 88% (14/16) of these patients, improvements occurred within six months of starting treatment. Only 2 of 48 patients had worsening in bone marrow fibrosis 38 of 116 (33%) patients with evaluable samples across all three treatment arms had a one grade or greater improvement in bone marrow fibrosis. In 84% (32/38) of these patients, improvements occurred within six months of treatment. Only 7 of 116 patients had worsening in bone marrow fibrosis Analysis of evaluable patient samples from MANIFEST suggests that CPI-0610 promotes normalization of megakaryocyte and erythroid differentiation and proliferation, which the Company believes may improve bone marrow function and hemoglobin levels, and may ultimately be disease-modifying in patients Safety: CPI-0610 was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients. Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (15%), anemia (13%), diarrhea (4%), constipation (2%), respiratory tract infection (2%), and decreased weight (2%). Other Grade 3/4 TEAEs (= 5%) include hyperuricemia (9%), hyperkalemia (6%) and dyspnea (6%). Nine patients discontinued treatment because of TEAEs. Among the most common TEAEs in 78 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (23%), anemia (10%), respiratory tract infections (5%), diarrhea (4%), asthenic conditions (4%), and nausea (3%). Grade 4 TEAEs included thrombocytopenia (3%) and anemia (1%). Nine patients discontinued treatment due to TEAEs, including six Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), disease progression, congestive heart failure, and transformation to AML. Among the most common TEAEs in 78 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (28%) and thrombocytopenia (5%). Grade 4 TEAEs included thrombocytopenia (3%), anemia (1%), and respiratory tract infection (1%). Two patients discontinued treatment due to TEAEs. In addition, there were two Grade 5 TEAEs, each resulting from multi-organ failure due to sepsis.