Pelabresib improves all four hallmarks of myelofibrosis in phase III MANIFEST-2 study.- MorphoSys AG.

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.

“The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis, including a significant reduction in spleen size – a key finding given the known association between spleen volume reduction and patient survival,” said Raajit K. Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies, and Director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center. “The comprehensive results presented at ASH also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated. These findings point to pelabresib and ruxolitinib as a potential paradigm-shifting first-line treatment of this debilitating disease.”

MANIFEST-2 Comprehensive Findings : MANIFEST-2 is a global, multicenter, double-blind, Phase III 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 greater than 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 greater than 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).></0.001).>

Improvement in Anemia : Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade greater than 3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade greater than 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 greater than 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.

“Anemia can reduce patients’ quality of life by causing severe fatigue and necessitating blood transfusions,” said Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. “In MANIFEST-2, patients receiving the combination therapy showed clear benefits on anemia, including greater hemoglobin levels, fewer red blood cell transfusions and fewer anemia and fatigue adverse events. Given its strong efficacy, safety profile and signs of disease modification, the pelabresib and ruxolitinib combination has the potential to become the new standard of care in the first-line treatment of myelofibrosis.”

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-alfa 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 greater than 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 (greater than 10%) hematologic TEAEs were anemia (43.9%; grade greater than 3: 23.1%), thrombocytopenia (32.1%; grade greater than 3: 9.0%) and platelet count decrease (20.8%; grade greater than 3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade greater than 3: 36.4%), thrombocytopenia (23.4%; grade greater than 3: 5.6%) and platelet count decrease (15.9%; grade greater than 3: 0.9%). 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 .

The four hallmarks of myelofibrosis – enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms – have a strong impact on a patient’s life. In MANIFEST-2, the combination of JAK and BET inhibition addressed all four of these hallmarks with the potential to modify the course of the disease,” said Tim Demuth, M.D., Ph.D., MorphoSys Chief Research and Development Officer. “We are confident that the comprehensive data package will provide impactful insights into the promising and well-tolerated combination of pelabresib and ruxolitinib. Our goal now is to bring this first-line therapy to patients with intermediate- and high-risk myelofibrosis as quickly as possible. We look forward to meeting with regulatory agencies regarding these data and are diligently preparing regulatory filings with the intention of submitting applications to the FDA and the European Medicines Agency in the middle of 2024.”