Scientist examining test tubes in tray
Scientist examining test tubes in tray

Pelabresib

About Pelabresib

Pelabresib is an investigational selective small-molecule therapy aimed at promoting anti-tumor activity. It is designed to inhibit bromodomain and extra-terminal domain (BET) proteins, which may downregulate genes implicated in blood cancers.


Pelabresib Inhibits BET Proteins
 

Illustrated diagram of intracellular pathways showing how pelabresib blocks BET-mediated gene expression.

 

The BET family of proteins, along with the JAK/STAT pathway, have been implicated in the development and progression of myelofibrosis. Both pathways may increase levels of pro-inflammatory cytokines and stimulate production of abnormal blood cell precursors called megakaryocytes. The BET family of proteins is therefore emerging as a promising therapeutic target whose modulation may alter the underlying cause of disease in myelofibrosis, with possible synergistic results alongside JAK inhibition.


The JAK–STAT Pathway and BET Proteins Have Been Implicated in the Development of Myelofibrosis
 

Illustrated diagram of intracellular pathways showing the pathophysiology of myelofibrosis fueled by both JAK- and BET-mediated pathways.

 

Pelabresib is currently being investigated as a treatment for myelofibrosis in the Phase 2 MANIFEST and Phase 3 MANIFEST-2 studies. Interim data from the Phase 2 MANIFEST study showed prolonged improvement in spleen size and symptom severity at and beyond 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these results, the Phase 3 MANIFEST-2 study is further investigating pelabresib in combination with the JAK inhibitor ruxolitinib in myelofibrosis patients who have not been previously treated with a JAK inhibitor (JAK inhibitor-naïve patients). 

The development of pelabresib was funded in part by The Leukemia and Lymphoma Society®.

About Pelabresib Active Clinical Trials

 

MANIFEST-2 – Phase 3 

Study Description

The Phase 3 MANIFEST-2 trial (NCT04603495) is a global, multicenter, double-blind, randomized study comparing pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in patients with myelofibrosis who have not previously been treated with a JAK inhibitor (JAK inhibitor-naïve patients). 

Topline results are expected by the end of 2023.

Endpoints

The primary endpoint of the study is the proportion of patients who achieve a 35% or greater reduction in spleen volume at week 24 (known as SVR35). Reduction in spleen size is an important clinical endpoint in myelofibrosis because spleen enlargement reflects disease activity and can cause significant pain and discomfort. 

The key secondary endpoint of the study is the proportion of patients achieving a 50% or greater improvement in total symptom score (TSS50), as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0, at week 24. MFSAF is a validated self-assessment tool designed specifically for patients with myelofibrosis that can track changes in symptoms such as severe fatigue, fever and weight loss that can diminish patients’ quality of life. A higher score indicates a higher disease burden and thus a worse outcome. 

In addition to these two endpoints, the study is also measuring the percent change in total symptom score at week 24, progression free survival, overall survival, duration of the splenic and total symptom score response, and improvement in bone marrow fibrosis, among others. 

Constellation Pharmaceuticals, Inc., a MorphoSys company, is the trial sponsor of the MANIFEST-2 study.
 

MANIFEST – Phase 2

Study Description

The Phase 2 MANIFEST trial (NCT02158858) is an open-label study of pelabresib in patients with myelofibrosis and high-risk essential thrombocythemia. 

MANIFEST is evaluating pelabresib in four arms:

  • Arm 1: Pelabresib as a monotherapy in patients who are resistant to, intolerant of or ineligible for ruxolitinib and no longer on the drug
  • Arm 2: Pelabresib as an add on therapy to ruxolitinib in patients with a suboptimal response to ruxolitinib or myelofibrosis progression
  • Arm 3: Pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve patients with myelofibrosis 
  • Arm 4: Pelabresib as a monotherapy in patients with high-risk essential thrombocythemia — another myeloproliferative disorder — who are intolerant of or refractory to hydroxyurea (a chemotherapy commonly used to treat the disease)

Endpoints

The primary endpoint in Arms 1 and 2 for patients who were transfusion-dependent at baseline is the proportion converting to transfusion-independence for 12 consecutive weeks. For those who were not transfusion-dependent at baseline, the primary endpoint is the proportion achieving SVR35 after 24 weeks of treatment.

The primary endpoint in Arm 3 is the proportion of patients achieving SVR35 after 24 weeks of treatment.

The primary endpoint for patients in Arm 4 is complete hematological response rate after one cycle, or 21 days, of treatment.  

Constellation Pharmaceuticals, Inc., a MorphoSys company, is the trial sponsor of the MANIFEST study.

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Pelabresib is currently not approved by regulatory authorities for the treatment of any disease anywhere in the world. It cannot be prescribed or purchased for therapy at present. The MorphoSys website may contain information on drug candidates and clinical trials sponsored by MorphoSys with the intention of increasing the transparency of the company’s clinical research. There is no guarantee any product will be approved in the sought-after indication. Information contained within this website is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. All reasonable precautions have been taken to ensure the accuracy, security, and confidentiality of information available through the site. MorphoSys may amend the information at any time without notice.