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Current Hematologic Malignancy Reports

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17-05-2023 | Ruxolitinib

Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis

Authors: Guadalupe Ferreira Gomes, Claire Harrison

Published in: Current Hematologic Malignancy Reports | Issue 4/2023

Abstract

Purpose of Review

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF.

Recent Findings

BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated.

Summary

Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

Takenaka K, Shimoda K, Akashi K. Recent advances in the diagnosis and management of primary myelofibrosis. Korean Journal of Internal Medicine. Korean Assoc Int Med. 2018;33:679–90.CrossRef

• Tremblay D, Mesa R. Novel treatments for myelofibrosis: beyond JAK inhibitors. Int J Hematol. 2022;115(5):645–58. https://doi.org/10.1007/s12185-022-03299-8. Review of the current growing treatment landscape in MF.CrossRefPubMed

Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2021;96(1):145–62.CrossRefPubMed

•• Harrison CN, Gupta VK, Gerds AT, Rampal R, Verstovsek S, Talpaz M, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol. 2022;18(27):2987–97. First Phase III study assessing combination therapy as first-line treatment for patients with MF without prior JAKi exposure.CrossRefPubMed

Stahl M, Zeidan AM. Management of myelofibrosis: JAK inhibition and beyond. Expert Rev Hematol. 2017;10:459–77.CrossRefPubMed

Tefferi A, Nicolosi M, Mudireddy M, Szuber N, Finke CM, Lasho TL, et al. Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients. Am J Hematol. 2018;93(3):348–55.CrossRefPubMed

Mascarenhas JO, Verstovsek S. The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes. Cancer. 2022;128:2717–27.CrossRefPubMed

Harrison C, Kiladjian JJ, Kathrin Al-Ali H, Gisslinger H, Waltzman R, Stalbovskaya V, et al. N Engl J Med 2012;366(9):787-798

Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-24.CrossRefPubMedPubMedCentral

10.

Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: A randomized clinical trial. JAMA Oncol. 2018;4(5):652–9.CrossRefPubMedPubMedCentral

11.

Fisher DAC, Miner CA, Engle EK, Hu H, Collins TB, Zhou A, et al. Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFκB signaling. Leukemia. 2019;33(8):1978–95.CrossRefPubMedPubMedCentral

12.

Palandri F, Breccia M, Bonifacio M, Polverelli N, Elli EM, Benevolo G, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. 2020;126(6):1243–52.CrossRefPubMed

13.

Alqahtani A, Choucair K, Ashraf M, Hammouda DM, Alloghbi A, Khan T, et al. Bromodomain and extra-terminal motif inhibitors: A review of preclinical and clinical advances in cancer therapy. Future Sci OA. 2019;5(3):2056–5623. https://doi.org/10.4155/fsoa-2018-0115.CrossRef

14.

• Kleppe M, Koche R, Zou L, van Galen P, Hill CE, Dong L, et al. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell. 2018;33(1):29–43. Preclinical evidence of synergistic activity of combination therapy with BET-inhibitor and JAKi for treatment of MF.CrossRefPubMed

15.

Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468(7327):1119–23.CrossRefPubMedPubMedCentral

16.

Stathis A, Bertoni F. BET Proteins as Targets for Anticancer Treatment. Cancer Discovery 2018;24–36. https://doi.org/10.1158/2159-8290.CD-17-0605.

17.

Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Co A, Leblanc Y, et al. Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials. J Med Chem. 2016;59:1330–9.CrossRefPubMed

18.

Peschke E, Mühlbauer E. New evidence for a role of melatonin in glucose regulation. Best Pract Res Clin Endocrinol Metab. 2010;24(5):829–41.CrossRefPubMed

19.

Espino J, Pariente J, Rodríguez A. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes. 2011;15(2):82–91.CrossRef

20.

Ceribelli M, Kelly PN, Shaffer AL, Wright GW, Xiao W, Yang Y, et al. Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors. Proc Natl Acad Sci USA. 2014;111(31):11365–70.CrossRefPubMedPubMedCentral

21.

Kremyanskaya M, Hoffman R, Mascarenhas J, Verstovsek S, Mertz J, Garner F, et al. A Phase 2 Study of Cpi-0610, a Bromodomain and Extraterminal (BET) Inhibitor, in Patients with Myelofibrosis (MF). Blood. 2018;132(Sup. 1):5481–5481. https://doi.org/10.1182/blood-2018-99-119157.CrossRef

22.

Ding N, Hah N, Yu RT, Sherman MH, Benner C, Leblanc M, et al. BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci USA. 2015;112(51):15713–8.CrossRefPubMedPubMedCentral

23.

Blum KA, Supko JG, Maris MB, Flinn IW, Goy A, Younes A, et al. A Phase I Study of Pelabresib (CPI-0610), a Small-Molecule Inhibitor of BET Proteins, in Patients with Relapsed or Refractory Lymphoma. Cancer Res Commun. 2022;2(8):795–805.CrossRefPubMedPubMedCentral

24.

• Kremyanskaya M, Mascarenhas J, Palandri F, Vannucchi A, Verstovsek S, Harrison CN, et al. Pelabresib (CPI-0610) Monotherapy in Patients with Myelofibrosis - Update of Clinical and Translational Data from the Ongoing Manifest Trial. Blood. 2021;138(Sup.1):141. https://doi.org/10.1182/blood-2021-150172. Report of the results of arm 1 (pelabresib monotherapy in JAKi intolerant/refractory patients) of the Manifest Trial.CrossRef

25.

•• Mascarenhas J, Kremyanskaya M, Patriarca A, Harrison C, Bose P, Rampal RK, et al. MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis - JAK Inhibitor-Naïve or With Suboptimal Response to Ruxolitinib - Preliminary Data From the MANIFEST Study. Clin Lymphoma Myeloma Leuk. 2022;22(Sup.2):335–6. Potentially practice changing data from MANIFEST trial in MF patients with suboptimal response to JAKi (arm 2) and JAKi-naïve (arm 3) treated with combination treatment of pelabresib and ruxolitinib.CrossRef

26.

• Harrison C, Kremyanskaya M, Bose P, Gupta V, Rampal RK, Lambert J, et al. Pelabresib (CPI-0610) As Add-on to Ruxolitinib in Myelofibrosis: Durability of Response and Safety Beyond Week 24 in the Phase 2 MANIFEST Study. Blood. 2022;140(Sup.1):9659–62. https://doi.org/10.1182/blood-2022-157735. Updated report of MANIFEST study arm 2 results of pelabresib as add-on to ruxolitinib.CrossRef

27.

•• Mascarenhas J, Kremyanskaya M, Patriarca A, Palandri F, Devos T, Passamonti F, et al. MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis. J Clin Oncol. 2023;1–13. Updated report of MANIFEST study arm 3 results confirming clinical efficacy and disease biomarker findings of combination treatment with pelabresib and ruxolitinib.

28.

Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. N Engl J Med. 2012;366(9):799–807.CrossRefPubMedPubMedCentral

29.

•• Zavidij O, Haradhvala NJ, Meyer R, Cui J, Verstovsek S, Oh S, et al. MPN-238 Single-Cell RNA Profiling of Myelofibrosis Patients Reveals Pelabresib-Induced Decrease of Megakaryocytic Progenitors and Normalization of CD4+ T Cells in Peripheral Blood. Clin Lymphoma Myeloma Leuk. 2022;22(Sup.2):S331-2. Report of pelabresib positive effects on potential disease biomarkers in MF patients.CrossRefPubMed

Title: Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis
Authors: Guadalupe Ferreira Gomes
Claire Harrison
Publication date: 17-05-2023
Publisher: Springer US
Keyword: Ruxolitinib
Published in: Current Hematologic Malignancy Reports / Issue 4/2023
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI: https://doi.org/10.1007/s11899-023-00696-6

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