Bromodomain and extraterminal (BET) proteins are key drivers of myelofibrosis pathogenesis and disease progression through modulation of the expression of key genes. Combination therapies are being explored to improve outcomes in myelofibrosis patients. A Phase III MANIFEST-2 trial showed adding pelabresib, a BET inhibitor being developed by MorphoSys, to ruxolitinib significantly increased spleen volume reduction compared to ruxolitinib alone. MANIFEST-2 is one of the largest studies in this indication to date. In February 2024, MorphoSys entered into a business combination agreement to be acquired by novartis for EUR 2.7 billion equity value. As part of this business combination agreement, Novartis seeks to obtain exclusive, worldwide rights to develop and commercialize pelabresib and tulmimetostat. 

At the EHA 2024 congress, two abstracts from the MANIFEST-2 study were unveiled. Abstract #S221 reported the latest findings on the safety and efficacy of combining pelabresib with ruxolitinib in JAK inhibitor-naïve myelofibrosis patients. Meanwhile, Abstract #S220 presented preliminary evidence of bone marrow recovery from the same study.

Abstract #S221: The MANIFEST-2 study met its primary endpoint, as the combination therapy demonstrated a statistically significant and clinically meaningful improvement in the proportion of patients achieving at least a 35% reduction in spleen volume (SVR35) at week 24. The key secondary endpoints assessing symptom improvement – proportion of patients achieving at least a 50% reduction in total symptom score (TSS50) and absolute change in total symptom score (TSS) from baseline at Week 24 showed a strong positive trend favoring the pelabresib and ruxolitinib combination. 

Get more insights of the report @ Myelofibrosis Market Size

For JAKi-naive myelofibrosis, the most recent data indicated that Pelabresib + Ruxolitinib vs. Placebo + Ruxolitinib demonstrated

• SVR35 response of  65.9% vs. 35.2% 

• Loss of SVR35 response of  13.4% vs 27.8% 

• Dual SVR35/TSS50  response of 40.2% vs 18.5%

There was ~2-fold difference in patients with dual SVR35 and TSS50 responses (40.2% vs 18.5%).

In terms of safety, significant BMF improvement ≥1 grade was reported in 38.5% patients at Week 24. Of 426 pts evaluated for safety, the most common treatment-emergent adverse events in the Pelabresib + Ruxolitinib were anemia, thrombocytopenia, platelet count decreased, and diarrhea. Mean (SD) time to onset of any grade treatment-emergent adverse effects (TEAEs) was 23.05 vs 28.23 days. 

Based on the strong and comprehensive data generated from the MANIFEST-2 study, MorphoSys will continue conversations with regulatory agencies, with intention to submit a New Drug Application for pelabresib in combination with ruxolitinib in myelofibrosis to the US FDA and a Marketing Authorization Application to the EMA in the middle of 2024.

Abstract #S220: Results show the potential of pelabresib + ruxolitinib to improve the four hallmarks of myelofibrosis, with significantly reduced splenomegaly, improved symptom score, improved anemia, and reduced bone marrow fibrosis.

At Week 24, treatment with pelabresib + ruxolitinib resulted in a significant reduction in NF-κB regulated proinflammatory cytokine levels compared to placebo + ruxolitinib. Reductions in cytokine levels correlated with SVR35 and TSS50 responses. Bone marrow analysis demonstrated a notable decrease in reticulin fiber density and megakaryocyte density in patients receiving pelabresib + ruxolitinib. Furthermore, while there was an increase in endothelial progenitor cell (EPC) proportions with pelabresib + ruxolitinib, a decrease was observed with placebo + ruxolitinib, particularly in patients who did not require red blood cell transfusions. Consistent with the previous findings, clinical outcomes suggest that pelabresib in combination with ruxolitinib could lead to more profound and durable clinical responses in patients with myelofibrosis.

Also, Read @ The Dynamic Landscape of Myelofibrosis Treatment: A 2024 Perspective

KOL insights

“We are very pleased with this positive outcome. Pelabresib in combination with ruxolitinib demonstrated strong reductions in spleen volume and symptoms over ruxolitinib monotherapy – the most impressive benefits seen in clinical studies of patients with myelofibrosis. Importantly, there was significant symptom improvements observed for the vast majority of patients in the study.”– MD, United States.

Conclusion 

Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. Combined BET and JAK inhibition therapy has potential for synergistic effects that may improve clinical outcomes for patients with myelofibrosis. This has been proven right with the encouraging findings from the MANIFEST-2 study that demonstrated improvements in all the hallmarks with the pelabresib and ruxolitinib combination treatment. 

Emerging Key players using RUXO as their combination might undoubtedly increase JAKAFI's market share. By the next year, or in 2025, it is anticipated that Pelabresib in combination with JAKAFI will receive regulatory approval. It will be advantageous for Incyte/Novartis if and when pelabresib combined with JAKAFI is authorized. If the drug's profile or combination matches how it appears in preliminary clinical data, many physicians may opt to utilize it, and JAKAFI will reap the rewards, but only real-world patterns and approval processes will provide a complete view. However, it is absolutely worthy to say that based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation. 

The Pelabresib-ruxolitinib combination in JAK inhibitor-naïve patients showed a statistically significant improvement in SVR35 response. The company is competing with AbbVie in the development of therapies that can be added to JAK inhibitors in first-line myelofibrosis therapies, including AbbVie’s BCL-2 inhibitor navitoclax, which is being tested in combination with JAKAFI in JAK inhibitor-naïve patients in the TRANSFORM-1 study.

Check more insights of the report @ Janus Kinase (JAK) Inhibitor Market Size

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