Pelabresib

Pelabresib
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
CAS Number	anhydrous: 1380087-89-7; monohydrate: 1845726-14-8;
3D model (JSmol)	anhydrous: Interactive image; monohydrate: Interactive image;
ChEBI	anhydrous: CHEBI:189653;
ChEMBL	anhydrous: ChEMBL4303404;
ChemSpider	anhydrous: 32738784;
DrugBank	anhydrous: DB17129;
IUPHAR/BPS	anhydrous: 9120;
KEGG	monohydrate: D12266;
PubChem CID	anhydrous: 57389999; monohydrate: 118591411;
UNII	anhydrous: U4017GUQ06; monohydrate: 306QR91I9R;
CompTox Dashboard (EPA)	anhydrous: DTXSID201022544 ;
	InChI 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;
	SMILES 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). Infobox references

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]

References

^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Constellation Pharmaceuticals (2024-10-28). An Open-Label, Multicenter, Extension Study for Patients Previously Enrolled in Studies with Pelabresib (Report). clinicaltrials.gov.

[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.

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