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
 

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
 

Pelabresib is currently being investigated in combination with the JAK inhibitor ruxolitinib compared with placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (those who have not been previously treated with a JAK inhibitor) in the Phase 3 MANIFEST-2 study and in Arm 3 of the Phase 2 MANIFEST study. A full list of the MANIFEST study arms can be found below. 

Beyond myelofibrosis, pelabresib has demonstrated potential clinical benefit in early-stage trials in other myeloid diseases. We look forward to investigating pelabresib further in lower-risk myelodysplastic syndromes (MDS) and essential thrombocytopenia (ET).

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

MANIFEST-2 – Phase 3 

Study Description

The Phase 3 MANIFEST-2 trial (NCT04603495) is a global, multicenter, double-blind study that randomized 430 JAK inhibitor-naïve adult patients with myelofibrosis 1:1 to receive pelabresib in combination with ruxolitinib or placebo plus ruxolitinib.

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 endpoints of the study are the absolute change in total symptom score from baseline at week 24 and the proportion of patients achieving a 50% or greater improvement in total symptom score (TSS50) from baseline at week 24. Total symptom score is measured by the Myelofibrosis Symptom Assessment Form (MF-SAF) v4.0, a validated self-assessment tool that asks patients to report the severity of seven common symptoms, rating each of them on a scale from 0 (absent) to 10 (worst imaginable).

Additional secondary endpoints include 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 with myelofibrosis 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.

Pelabresib is an investigational agent; its safety and efficacy have not been established. 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.