Announcement • Dec 11
MorphoSys AG’ Pelabresib Improves All Four Hallmarks of Myelofibrosis in Phase 3 MANIFEST-2 Study
MorphoSys AG announced comprehensive results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. These findings were presented in an oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. In MANIFEST-2, all hallmarks were improved with the pelabresib and ruxolitinib combination versus placebo plus ruxolitinib, which is the standard of care in myelofibrosis. Ruxolitinib dosing was similar in both arms of the study and was determined based on its approved myelofibrosis indication. MANIFEST-2 Comprehensive Findings: MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized 1:1 to receive the pelabresib and ruxolitinib combination or placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies in this disease to date. Strong Reductions in Spleen Size and Symptoms: In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated a near doubling in the proportion of patients achieving a =35% reduction in spleen volume (SVR35) at 24 weeks, the primary endpoint, versus placebo plus ruxolitinib (p<0.001). For the first key secondary endpoint assessing symptom reduction, absolute change in total symptom score (TSS) at 24 weeks, there was a strong numerical improvement for patients receiving pelabresib and ruxolitinib versus placebo plus ruxolitinib. The response rate for the second key secondary endpoint, proportion of patients achieving =50% reduction in symptom score (TSS50) at 24 weeks, was also numerically greater for patients receiving pelabresib and ruxolitinib. Significant improvements in both key secondary endpoints were observed with the pelabresib combination for patients classified as intermediate-risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2), who account for over 90% of the MANIFEST-2 population. The proportion of patients achieving both SVR35 and TSS50 at 24 weeks was doubled with pelabresib and ruxolitinib versus placebo plus ruxolitinib (40.2% vs. 18.5%, respectively). Improvement in Anemia: Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade =3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade =3: 36.4%). Additionally, by week 24, fewer patients in the pelabresib and ruxolitinib arm required red blood cell transfusions compared with the placebo arm (30.8% vs. 41.2%, respectively). A greater proportion of patients achieved a hemoglobin response — defined as a =1.5 g/dL mean increase in hemoglobin levels over baseline in the absence of transfusions during the previous 12 weeks — with pelabresib and ruxolitinib versus placebo plus ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin levels were greater in patients receiving pelabresib and ruxolitinib than in those receiving placebo plus ruxolitinib, starting at week 9 and continuing to week 24. Anemia benefits were observed across all studied patient risk groups. Improvement in Bone Marrow Fibrosis: Bone marrow fibrosis, or the replacement of bone marrow with fibrous scar tissue, is a central pathological feature of myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one grade in a greater proportion of patients receiving pelabresib and ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and worsened by at least one grade in a smaller proportion of patients receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a scale from 0 (normal) to 3 (most severe) based on fiber density; studies suggest a correlation between the grade of bone marrow fibrosis and patient prognosis. Biomarker Analysis Suggests Disease Modification: In a biomarker analysis, average plasma levels of inflammatory cytokines (IL-8, IL-6, TNF-a and NF-?B-regulated cytokines) were reduced in patients receiving pelabresib and ruxolitinib compared with placebo plus ruxolitinib at 24 weeks. Increased cytokine levels are associated with all four disease hallmarks; increased IL-8 levels are also associated with worse survival outcomes. These biomolecular improvements suggest early evidence of a disease-modifying effect. Well-Tolerated Safety Profile: Overall, grade =3 treatment-emergent adverse events (TEAEs) were reported less frequently with pelabresib and ruxolitinib than with placebo plus ruxolitinib (49.1% vs. 57.5%, respectively). In the pelabresib and ruxolitinib arm, the most common (=10%) hematologic TEAEs were anemia (43.9%; grade =3: 23.1%), thrombocytopenia (32.1%; grade =3: 9.0%) and platelet count decrease (20.8%; grade =3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade =3: 36.4%), thrombocytopenia (23.4%; grade =3: 5.6%) and platelet count decrease (15.9%; grade =3: 0.9%). The most common (=10%) nonhematologic TEAEs in the pelabresib and ruxolitinib arm were diarrhea (23.1%; grade =3: 0.5%), dysgeusia (18.4%; grade =3: 0.5%), constipation (18.4%; grade =3: 0%), nausea (14.2%; grade =3: 0.5%), cough (12.7% grade =3: 0), asthenia (11.8% grade =3: 0.5%), fatigue (11.8%; grade =3: 0.5%), dizziness (11.3%; grade =3: 0%), headache (11.3% grade =3: 0.5%) and COVID-19 (11.3%; grade =3: 0%). The most common nonhematologic TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%; grade =3: 0%), diarrhea (18.7%; grade =3: 1.4%), fatigue (16.8%; grade =3: 0.9%), COVID-19 (15.9%; grade =3: 1.9%), nausea (15.0%; grade =3: 0%), asthenia (13.6%; grade =3: 0%), dyspnea (13.1%; grade =3: 0.9%), cough (11.2%; grade =3: 0%) and headache (10.7%; grade =3: 0%). Discontinuation rates due to adverse events were 10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus ruxolitinib. The safety profile of the pelabresib and ruxolitinib combination therapy was consistent with previous clinical studies. No new safety signals were observed.