Pelabresib

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Pelabresib
CPI-0610 structure.png
Names
IUPAC name
2-[(4S)-6-(4-chlorophenyl)-1-methyl-4H-[1,2]oxazolo[5,4-d][2]benzazepin-4-yl]acetamide
Other names
CPI-0610
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
KEGG
PubChem CID
UNII
  • InChI=1S/C20H16ClN3O2/c1-11-18-14-4-2-3-5-15(14)19(12-6-8-13(21)9-7-12)23-16(10-17(22)25)20(18)26-24-11/h2-9,16H,10H2,1H3,(H2,22,25)/t16-/m0/s1
    Key: GCWIQUVXWZWCLE-INIZCTEOSA-N
  • monohydrate:InChI=1S/C20H16ClN3O2.H2O/c1-11-18-14-4-2-3-5-15(14)19(12-6-8-13(21)9-7-12)23-16(10-17(22)25)20(18)26-24-11;/h2-9,16H,10H2,1H3,(H2,22,25);1H2/t16-;/m0./s1
    Key: LXMGXMQQJNULPR-NTISSMGPSA-N
  • anhydrous:CC1=NOC2=C1C3=CC=CC=C3C(=N[C@H]2CC(=O)N)C4=CC=C(C=C4)Cl
  • monohydrate:CC1=NOC2=C1C3=CC=CC=C3C(=N[C@H]2CC(=O)N)C4=CC=C(C=C4)Cl.O
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pelabresib (CPI-0610; PELA) is an investigational oral small-molecule drug designed to inhibit bromodomain and extra-terminal domain (BET)-mediated gene transcription involved in myelofibrosis pathogenesis. [1] [2]

Description

A phase one study of pelabresib in patients with relapsed/refractory lymphomas found pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily. [3] [4]

In MANIFEST-2, a phase three, randomized, blinded study compares pelabresib and ruxolitinib with placebo and ruxolitinib in myelofibrosis patients that have not been previously treated with Janus kinase inhibitors (JAKi). [5] [6]

NCT02158858, a phase one/two open-label, sequential dose escalation study of pelabresib in patients with previously treated acute leukemia, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, and myelofibrosis is ongoing. [7]

A third study, NCT06401356, is ongoing to provide continued access to treatment with pelabresib for patients who previously received pelabresib in a parent study and to continue collecting safety and efficacy information, such as a patient's leukemia-free survival and overall survival status during and after the treatment is ended. [8]

Related Research Articles

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Overproduction of blood cells in the bone marrow

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

<span class="mw-page-title-main">Tipifarnib</span> Chemical compound

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

<span class="mw-page-title-main">Decitabine</span> Medication for the treatment of conditions where certain blood cells are dysfunctional,

Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.

<span class="mw-page-title-main">Lestaurtinib</span> Chemical compound

Lestaurtinib is a tyrosine kinase inhibitor structurally related to staurosporine. This semisynthetic derivative of the indolocarbazole K252a was investigated by Cephalon as a treatment for various types of cancer. It is an inhibitor of the kinases fms-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), tropomyosin receptor kinase (trk) A (TrkA), TrkB and TrkC.

<span class="mw-page-title-main">Omacetaxine mepesuccinate</span> Chemical compound

Omacetaxine mepesuccinate is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML).

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Obatoclax</span> Chemical compound

Obatoclax mesylate, also known as GX15-070, is an experimental drug for the treatment of various types of cancer. It was discovered by Gemin X, which was acquired by Cephalon, which has since been acquired by Teva Pharmaceuticals. Several Phase II clinical trials were completed that investigated use of obatoclax in the treatment of leukemia, lymphoma, myelofibrosis, and mastocytosis.

<span class="mw-page-title-main">Fedratinib</span> Chemical compound

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.

<span class="mw-page-title-main">Momelotinib</span> Medication

Momelotinib, sold under the brand name Ojjaara among others, is an anticancer medication used for the treatment of myelofibrosis. It is a Janus kinase inhibitor and it is taken by mouth.

Ligelizumab is a humanized IgG1 monoclonal antibody designed for the treatment of severe asthma and chronic spontaneous urticaria. It is an anti-IgE that binds to IGHE an acts as an immunomodulator. It is delivered as a subcutaneous biologic injection.

<span class="mw-page-title-main">Apabetalone</span> Chemical compound

Apabetalone is an orally available small molecule created by Resverlogix Corp. that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD). In the phase II clinical trial ASSURE in patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels, apabetalone showed no greater increase in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels or incremental regression of atherosclerosis than administration of placebo, while causing a statistically significant greater incidence of elevated liver enzymes. However, pooled analysis of the effect of apabetalone in three phase II clinical trials ASSERT, ASSURE, and SUSTAIN demonstrated increases in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreases in the incidence of major adverse cardiac events (MACE). Reduction of MACE was more profound in patients with diabetes mellitus. In a short-term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone. An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015. The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.

BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.

Evenamide is a selective voltage-gated sodium channel blocker, including subtypes Nav1.3, Nav1.7, and Nav1.8, which is described as an antipsychotic and is under development by Newron Pharmaceuticals as an add-on therapy for the treatment of schizophrenia. The drug has shown efficacy in animal models of psychosis, mania, depression, and aggression. It has completed phase I clinical trials, and phase II clinical trials will be commenced in the third quarter of 2015.

<span class="mw-page-title-main">Pevonedistat</span> Chemical compound

Pevonedistat (MLN4924) is a selective NEDD8 inhibitor. It is being investigated as a cancer treatment, e.g. for mantle cell lymphoma (MCL).

<span class="mw-page-title-main">Gandotinib</span> Chemical compound

Gandotinib (LY-2784544) is an experimental drug developed by Eli Lilly for treatment of cancer. It is a small molecule JAK2 inhibitor, with additional minor inhibition of STAT3.

<span class="mw-page-title-main">Devimistat</span> Chemical compound

Devimistat is an experimental anti-mitochondrial drug being developed by Cornerstone Pharmaceuticals. It is being studied for the treatment of patients with metastatic pancreatic cancer and relapsed or refractory acute myeloid leukemia (AML).

Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate of progression is variable and not all patients progress. Symptoms and presentation can mimic essential thrombocythemia, with the main differentiator for pre-PMF being the presence of fibrosis in the bone marrow.

<span class="mw-page-title-main">Jaktinib</span> Chemical compound

Jaktinib is a janus kinase inhibitor under development for myelofibrosis. It is a deuterated-drug analog of momelotinib.

References

  1. Rampal, Raajit; Grosicki, Sebastian; Chraniuk, Dominik; Abruzzese, Elisabetta; Bose, Prithviraj; Gerds, Aaron Thomas; Vannucchi, Alessandro M.; Palandri, Francesca; Lee, Sung-Eun; Gupta, Vikas; Lucchesi, Alessandro; Kuykendall, Andrew Tucker; Mesa, Ruben A.; Kiladjian, Jean-Jacques; Talpaz, Moshe (2024-05-29). "Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naïve patients with myelofibrosis". Journal of Clinical Oncology. 42 (16_suppl): 6502. doi:10.1200/JCO.2024.42.16_suppl.6502. ISSN   0732-183X.
  2. Mascarenhas, John; Kremyanskaya, Marina; Patriarca, Andrea; Gupta, Vikas; Palandri, Francesca; Devos, Timothy; Rampal, Raajit K; Talpaz, Moshe; Vannucchi, Alessandro; Kuykendall, Andrew; Kiladjian, Jean-Jacques; Verstovsek, Srdan; Mesa, Ruben; Colak, Gozde; Li, Qing (2022-11-15). "Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24". Blood. 140 (Supplement 1): 586–589. doi:10.1182/blood-2022-158147. ISSN   0006-4971. Archived from the original on 2024-06-10. Retrieved 2024-11-29.
  3. Constellation Pharmaceuticals (2024-05-07). A Phase 1 Study of CPI-0610, a Small Molecule Inhibitor of BET (Bromodomain and Extra-terminal) Proteins, in Patients With Progressive Lymphoma (Report). clinicaltrials.gov. Archived from the original on 2024-06-04. Retrieved 2024-11-29.
  4. Verstovsek, Srdan; Salama, Mohamed E; Mascarenhas, John; Talpaz, Moshe; Mesa, Ruben A.; Vannucchi, Alessandro; Rampal, Raajit; Oh, Stephen T.; Olteanu, Horatiu; Chiu, April; Chen, Dong; Hanson, Curtis A.; Curto-Garcia, Natalia; Taverna, Pietro; Cui, Jike (2021-11-23). "Disease-Modifying Potential of BET Inhibitor Pelabresib (CPI-0610) As Demonstrated By Improvements in Bone Marrow Function and Clinical Activity in Patients with Myelofibrosis - Preliminary Data". Blood. 138: 2568. doi:10.1182/blood-2021-152267. ISSN   0006-4971.
  5. Constellation Pharmaceuticals (2024-10-25). A Phase 3, Randomized, Double-blind, Active-Control Study of Pelabresib (CPI-0610) and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients (Report). clinicaltrials.gov. Archived from the original on 2024-10-05. Retrieved 2024-11-29.
  6. Ferreira Gomes, Guadalupe; Harrison, Claire (2023-08-17). "Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis". Current Hematologic Malignancy Reports. 18 (4): 113–120. doi:10.1007/s11899-023-00696-6. ISSN   1558-822X. PMID   37195585.
  7. Constellation Pharmaceuticals (2024-10-31). A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis and Essential Thrombocytopenia) (Report). clinicaltrials.gov.
  8. Constellation Pharmaceuticals (2024-10-28). An Open-Label, Multicenter, Extension Study for Patients Previously Enrolled in Studies with Pelabresib (Report). clinicaltrials.gov.