What Is Pelabresib?
Pelabresib is an investigational medication being studied for various cancers. It is classified as a small molecule inhibitor of bromodomain and extraterminal (BET) proteins. BET proteins play a role in regulating gene expression, including genes involved in cell growth and inflammation. By inhibiting these proteins, pelabresib aims to disrupt disease progression in conditions where BET proteins are overactive.
Pelabresib is currently not FDA-approved for any condition. It is under investigation in 8 clinical trials sponsored by Novartis Pharmaceuticals and Constellation Pharmaceuticals, with a total enrollment of 1,365 participants. These trials are exploring its potential to treat a range of conditions, including advanced malignancies, solid tumors, and various hematological diseases, most notably myelofibrosis. The earliest trial for pelabresib began on June 9, 2014, with the latest trial projected to conclude in 2026.
Uses and Conditions Under Study
Pelabresib is being investigated for several types of cancer, primarily focusing on blood cancers and advanced solid tumors. Its mechanism as a BET inhibitor suggests it may interfere with cancer cell growth and survival across different malignancies.
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Myelofibrosis: This is a chronic bone marrow disorder where scar tissue builds up, impairing the body's ability to produce blood cells. Pelabresib is being studied for Myelofibrosis, Primary Myelofibrosis, and Primary Myelofibrosis (PMF) in a total of 2 trials. As a BET inhibitor, it may help reduce the inflammation and abnormal cell proliferation characteristic of this disease.
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Advanced Malignancies and Solid Tumors: Pelabresib is being evaluated for its effectiveness in treating advanced malignancies and solid tumors in a combined total of 5 trials (3 for advanced malignancies, 2 for solid tumors). These conditions represent cancers that have spread or are difficult to treat with standard therapies. The drug's ability to target gene expression pathways could be beneficial in controlling tumor growth.
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Hematological Diseases: This category includes various cancers affecting the blood, bone marrow, and lymph nodes. Pelabresib is under investigation for Hematological Disease, Hematological Malignancy, Leukemia, Acute Myelocytic Leukemia, and Myelodysplastic Syndrome (MDS) across a total of 5 trials. These conditions often involve uncontrolled growth of abnormal blood cells, which BET inhibition may help to regulate.
Dosing
Pelabresib has been studied in clinical trials as monohydrate tablets for oral administration. Various dosing regimens have been investigated, often involving daily administration followed by a break period.
Specific dosages studied include:
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125 mg orally once daily (QD) for 14 days, followed by a 7-day break. This regimen is also described as 125 mg orally once daily (QD) on Days 1-14 of each 21-day cycle.
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225 mg orally once daily (QD) for 14 days, followed by a 7-day break.
Pelabresib has been studied both as a single agent (monotherapy) and in combination with other medications. One notable combination regimen involves Pelabresib + Ruxolitinib. These studies have explored different treatment arms, including those for patients with prior JAK inhibitor monotherapy, prior JAK inhibitor combination therapy, and JAK inhibitor-naïve patients, particularly in the context of myelofibrosis. Dosage forms studied also include different arms for normal hepatic function versus moderate or severe hepatic impairment, indicating consideration for patient-specific factors.
Side Effects
In a clinical trial involving 212 patients taking Pelabresib, the most common side effect was anemia, affecting 42.5% of patients. This was compared to 54.2% of patients who received a placebo.
Other common side effects reported in patients taking Pelabresib, compared to placebo, included:
- Thrombocytopenia (low platelet count): 32.1% on Pelabresib vs. 23.4% on placebo.
- Diarrhea: 23.1% on Pelabresib vs. 18.2% on placebo.
- Decreased platelet count: 20.8% on Pelabresib vs. 15.9% on placebo.
- Constipation: 18.4% on Pelabresib vs. 24.3% on placebo.
- Dysgeusia (altered taste): 18.4% on Pelabresib vs. 3.7% on placebo.
- Nausea: 14.2% on Pelabresib vs. 15.0% on placebo.
- Cough: 12.7% on Pelabresib vs. 11.2% on placebo.
- Asthenia (lack of energy): 11.8% on Pelabresib vs. 14.0% on placebo.
- Fatigue: 11.8% on Pelabresib vs. 15.9% on placebo.
Some side effects, such as anemia, constipation, nausea, asthenia, and fatigue, were reported less frequently in patients taking Pelabresib compared to those on placebo. However, thrombocytopenia, diarrhea, decreased platelet count, dysgeusia, cough, dizziness, and headache were reported more frequently with Pelabresib.
Clinical Trial Results
Myelofibrosis (MF)
A Phase 3 study, NCT04603495 (MANIFEST-2), investigated Pelabresib in combination with ruxolitinib for the treatment of myelofibrosis. Approximately 300 participants received Pelabresib plus ruxolitinib, and approximately 300 participants received placebo plus ruxolitinib.
Key findings from the study at Week 24 include:
- Splenic Response: A significant number of patients experienced a reduction in spleen size. 141 participants (approximately 47%) in the Pelabresib plus ruxolitinib group achieved a splenic response, meaning a reduction of at least 35% in spleen volume, compared to 76 participants (approximately 25%) in the placebo plus ruxolitinib group.
- Total Symptom Score (TSS) Reduction: More patients on Pelabresib plus ruxolitinib experienced a substantial improvement in their myelofibrosis symptoms. 112 participants (approximately 37%) in the Pelabresib combination arm achieved a TSS50 response (at least a 50% reduction in total symptom score), compared to 100 participants (approximately 33%) in the placebo combination arm. This indicates a greater proportion of patients experienced meaningful symptom relief with Pelabresib.
- Overall Symptom Improvement: Patients treated with Pelabresib plus ruxolitinib showed a mean reduction in their Total Symptom Score of -15.99 points from baseline, indicating greater symptom improvement compared to a -14.05 point reduction in the placebo combination group. The average percentage change from baseline in TSS was also greater with Pelabresib, showing a -50.3% reduction in symptoms compared to -45.9% with placebo, further supporting the benefit in symptom management.
- Bone Marrow Fibrosis Improvement: Improvement in bone marrow fibrosis of at least one grade was observed in 36 participants (approximately 12%) receiving Pelabresib plus ruxolitinib, compared to 21 participants (approximately 7%) receiving placebo plus ruxolitinib. This suggests a potential positive impact on the underlying disease pathology.
Regarding red blood cell transfusions, the rate over the first 24 weeks of treatment was slightly higher in the Pelabresib plus ruxolitinib group (1.359 units transfused per patient-month) compared to the placebo plus ruxolitinib group (1.014 units transfused per patient-month).
Currently Recruiting Trials
Pelabresib is currently being investigated in several clinical trials, offering opportunities for patients to contribute to the understanding of this potential new treatment. These studies explore its effectiveness and safety, particularly for various forms of myelofibrosis and other advanced malignancies. One significant study, NCT07357727, is a Phase 3 trial sponsored by Novartis Pharmaceuticals. This study aims to enroll up to 460 participants with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF). It evaluates whether combining pelabresib with ruxolitinib leads to better clinical outcomes compared to ruxolitinib alone. Another trial, NCT07422610, is a Phase 1 study focusing on the pharmacokinetics and safety of pelabresib. This Novartis-sponsored trial targets 24 participants with advanced malignancies and either hepatic impairment or normal liver function. Its primary goal is to understand how liver function affects the body's processing of pelabresib. For Japanese adult patients with myelofibrosis, a Phase 1 study, NCT07340138, is underway. This multicenter, open-label trial, also sponsored by Novartis, plans to enroll 6 participants with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF). It will assess the safety, pharmacokinetics, and preliminary efficacy of pelabresib when added to ruxolitinib. Finally, an extension study, NCT06401356, is open for patients who have previously participated in other pelabresib studies. This Phase 3 trial, sponsored by Novartis, intends to enroll 50 participants with hematologic malignancy, solid tumors, or advanced malignancies. Its purpose is to evaluate the long-term safety and continued clinical benefit of pelabresib.Where to Participate
Opportunities to participate in Pelabresib clinical trials are currently available across 7 sites located in 6 cities and 6 states within the United States. These locations offer a chance for eligible patients to contribute to the ongoing research. Top participating locations include:- New York, New York (2 sites)
- Los Angeles, California
- Jacksonville, Florida
- Chicago, Illinois
- Ann Arbor, Michigan
- Berkeley Heights, New Jersey