On June 11, 2021 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported that three posters relating to the MANIFEST clinical trial of pelabresib (CPI-0610) in myelofibrosis (MF) were published online in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting (Press release, Constellation Pharmaceuticals, JUN 11, 2021, View Source [SID1234583890]). The data in these posters are based on a data cutoff of September 29, 2020 from the MANIFEST Phase 2 clinical trial and reflect an analysis of pelabresib clinical and translational activity.

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"We are particularly enthusiastic about the publication of centrally reviewed translational data, which describe early improvements in bone marrow fibrosis in patients treated with pelabresib, and we believe these results support our thesis of disease-modifying treatment effects that go beyond symptom management," said Patrick Trojer, chief scientific officer of Constellation Pharmaceuticals. "We are currently enrolling patients in the Phase 3 pivotal study of MANIFEST-2 and our goal is to transform the standard of care for the treatment of myelofibrosis."

Data Highlights

Translational data, across all three arms of the Phase 2 MANIFEST study, support the disease-modifying potential of pelabresib

Centrally reviewed bone marrow fibrosis (BMF) pathology conducted in 63 patients showed similar improvements as reported previously for local review of BMF grade. 23 out of 63 patients (37%) achieved at least a 1 grade improvement in BMF. Of these patients, 83% achieved improvements in BMF by 24 weeks.
17% of the patients with BMF improvement (4 out of 23), improved by at least 2 grades.
31 out of 63 patients (49%) were stabilized or had no change, and only 4 out of 63 patients (6%) worsened.
An increase in BM erythroid progenitor cells and reduction of the number and cluster formation of megakaryocytes in the BM was observed in 59% and 65%, respectively, of 37 samples from patients treated with pelabresib either as a monotherapy or in combination with ruxolitinib.
Pelabresib durably reduced inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha) and interleukin 18 (IL18) as early as 2 weeks and maintained through 24 weeks of treatment, based on an analysis of patient samples.
Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients

As previously reported at ASH (Free ASH Whitepaper) 2020, 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total Symptom Scores (TSS50) at 24 weeks.
Strong response was observed with pelabresib, irrespective of baseline risk status or demographic and disease characteristics.
Central pathology review of 27 1L patient bone marrow samples showed at least a one-grade improvement in bone marrow fibrosis in 9 out of 27 patients (33%); in all of these patients, improvement was observed within 6 months of starting treatment. 16 out of 27 patients (59%) showed stabilization of bone marrow fibrosis, while only 1 out of 27 patients (4%) showed worsening.
Arm 1 and 2 (2L) – Interim analysis demonstrating that pelabresib monotherapy in JAK-inhibitor-experienced or -ineligible patients, and with pelabresib + ruxolitinib in ruxolitinib-experienced patients, resulted in improvements in anemia

As previously reported at ASH (Free ASH Whitepaper) 2020, 3 of 14 evaluable Transfusion Dependent (TD) patients (21%) in Arm 1A achieved transfusion independence (the primary endpoint for arms 1A and 2A) and 13 of 36 evaluable TD patients (36%) in Arm 2A achieved transfusion independence.
9 out of 15 evaluable TD patients (60%) in Arm 1A, and 25 out of 47 of evaluable TD patients (53%) in Arm 2A achieved a ≥50% reduction in red blood cell transfusions.
Safety

As of the September 29, 2020 data cutoff, pelabresib 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 weight decrease (2%). Amongst the most common TEAEs, there were no Grade 4. Other Grade 3/4 TEAEs (≥5%) include hyperuricemia (9%), hyperkalemia (7%) and dyspnea (7%). Nine patients discontinued treatment because of TEAEs. No Grade 5 events were observed.

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%). Amongst the most common TEAEs, Grade 4 events 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%). Amongst the most common TEAEs, Grade 4 events 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.

EHA Poster Presentations

TITLE: Pelabresib (CPI-0610) improved anemia associated with myelofibrosis: interim results from MANIFEST Phase 2 study (Abstract Code: EP1077)

TITLE: Clinical benefit of pelabresib (CPI-0610) in combination with ruxolitinib in JAK-inhibitor treatment naïve myelofibrosis patients: Interim efficacy subgroup analysis from Arm 3 of MANIFEST Phase 2 study (Abstract Code: EP1085)

TITLE: BET inhibitor pelabresib decreases inflammatory cytokines, improves bone marrow fibrosis and function, and demonstrates clinical response irrespective of mutation status in myelofibrosis patients (Abstract Code: EP1080)

Date and Time: June 11, 9:00 AM CEST/ 3:00 AM EDT

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation Pharmaceuticals is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.