The MANIFEST 2 Trial: Pelabresib and Ruxolitinib

Myelofibrosis is often traceable by 4 clinical characteristics: bone marrow fibrosis (the development of scar tissue inside bones), anemia, an enlarged spleen, and other disease-associated symptoms. Scientists have linked these symptoms to two important groups of proteins involved in myelofibrosis: JAK/STAT and BET. Normally, these proteins help cells communicate and function properly. However, in myelofibrosis, these pathways malfunction:

• JAK-STAT Pathway: Imagine this pathway as a series of messengers inside a cell. In myelofibrosis, these messengers get stuck in the "on" position, causing the cell to grow and divide uncontrollably.
• BET Proteins: These proteins act like switches that control how much of a specific protein is made by a gene. In myelofibrosis, these switches might be malfunctioning, leading to the production of abnormal proteins that contribute to the disease.

What is Pelabresib?

Pelabresib is a selective small molecule created to promote anti-tumor activity by regulating particular signals and genes involved in the myelofibrosis pathway. It is designed to inhibit BET proteins and is being studied for the treatment of myelofibrosis and other myeloproliferative neoplasms (MPN).

The most frequent side effects of pelabresib are fatigue, nausea, constipation, thrombocytopenia (low platelet count), vomiting, febrile neutropenia (a fever and low counts of a white blood cell type called neutrophil), and diarrhea.

The MANIFEST-2 Trial

Results from the Phase 3 MANIFEST-2 trial (​​NCT04603495) with 430 patients who JAK inhibitor-naïve adult patients who received pelabresib in combination with ruxolitinib (this drug has previously been the standard of care for myelofibrosis treatment). MANIFEST-2 is one of the largest studies of myelofibrosis to date.

Initial Reported Results

The primary endpoint showed that after 24 weeks, patients showed an average of 66% reduction in spleen volume with the combination compared to ruxolitinib alone. They also reported a 50% reduction in Total Symptom Score [TSS]. These findings indicate that pelabresib and ruxolitinib could potentially revolutionize the initial treatment of this debilitating disease.

The study also showed:

• An improvement in anemia rates: fewer patients required transfusions.
• Improved bone marrow fibrosis by at least 1 point. (Studies suggest the grade of bone marrow fibrosis correlates with a patient’s prognosis.)
• Fewer number of disease symptom events.
• Plasma levels of inflammatory cytokines were reduced.

This study continued to monitor patients and will share new, updated, and longer-term results next week at the American Society of Cancer Oncology (ASCO) Annual Meeting. Join the HealthTree for Myelofibrosis community to stay updated!

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