Recent. MANIFEST-2: CPI-0610 Shows Benefit in Myelofibrosis. Jennifer A Mertz, PhD 1 *, Patricia J Keller,. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). CPI-0610 in MANIFEST, both as monotherapy and in combination with ruxolitinib and in both JAK-inhibitor-naïve and JAK-inhibitor-experienced and -ineligible patients, was generally well tolerated. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. BET proteins are known to promote cancer growth. Besides CPI-0610, these include the phosphatidylinositol-3-kinase delta isoform inhibitors parsaclisib 20 and umbralisib, 21 the BH3-mimetic navitoclax, the heat shock protein 90 antagonist PU-H71, etc. 35. , Blum K. Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. A minimum 2-week period between the last treatment with a therapeutic antibody and the first dose of CPI-0610 may be permitted in patients with rapidly progressive or aggressive subtypes of lymphoma following discussion with the medical monitor. Continued high rate of SVR35 in 1L patients: 72% at 12 weeks and 67% at 24 weeksSVR35 responses and transfusion dependence conversion observed in. Constellation's two lead product candidates, pelabresib (CPI-0610), a BET inhibitor, and CPI-0209, a second-generation EZH2 inhibitor, are in mid- to late-stage clinical trials and have broad therapeutic potential to offer meaningful benefits to patients with various hematological and solid tumors. Clinical data presented at 2019 American Society of Hematology annual meeting suggested that CPI-0610 could offer meaningful benefits beyond standard of care in myelofibrosis In addition to. The Grade 3 and 4 TEAEs were mostly hematological with anemia being the most commonly recorded Grade 3 TEAE. Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). CPI-0610 is still valuable to pursue with a larger group of patients who are more diverse in baseline characteristics to get a better idea of the response to this agent. In addition, the first dose of CPI-0610 should not occur before a period equal to or greater than 5 half-lives of the small molecule investigational agent has elapsed. We would like to show you a description here but the site won’t allow us. MANIFEST TrialMascarenhas served as lead author of a study presented at the 2022 European Hematology Association (EHA) Congress, titled, “BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in. Abramson JS, Blum KA, Flinn IW, et al. Download scientific diagram | BET bromodomain inhibitor molecules. ConclusionsPelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. For example, patients experienced immune responses, improvements in quality of life, and an occasional. Pelabresib (CPI-0610) Selective benzoisoxaoloazepine BET bromodomain inhibitor for BRD4-BD1 : NSD3 NSD3: AZD 5153 6-hydroxy 2-naphthoic acid ZEN-3694: Orally available BET-BRD4 bromodomain inhibitor Orally available pan-BET bromodomain inhibitor Context: Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. , et al. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC . To further dissect the underlying mechanism of these relative improvements in bone marrow composition and histotopography induced by CPI-0610, CD34+ hematopoietic stem cells were isolated from peripheral blood collected from multiple MF patients at baseline to evaluate the impact of CPI-0610 on MK and erythroid differentiation in vitro. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. 07) Dates. Besides CPI-0610, these include the phosphatidylinositol-3-kinase delta isoform inhibitors parsaclisib 20 and umbralisib, 21 the BH3-mimetic navitoclax, the heat shock protein 90 antagonist PU-H71, etc. CPI-0610, is an oral inhibitor of bromodomain and extraterminal domain (BET) proteins that inhibits cytokine production and promotes megakaryocytic and erythroid differentiation. 2018; 29:Pelabresib (CPI-0610) is an investigational, orally administered, small molecule BET inhibitor that reduces expression of BET target genes and modulates NF-κB signaling. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in myelofibrosis (MF). Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. A potent, oral small-molecule bromodomain and extraterminal domain (BET) inhibitor—CPI-0610—improves spleen volume and symptoms when added to the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) in ruxolitinib-naïve patients with myelofibrosis. CPI-0610 7. Haematologica. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [33]. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the. Blood. We would like to show you a description here but the site won’t allow us. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume. For a discussion of other risks and uncertainties, any of. Human Immunology Biosciences (HI-Bio) obtained exclusive worldwide rights to develop and commercialize MOR210 across all indications worldwide, with the exception of Greater China and South. 2217/epi-2019-0274. Phone Number: 1-877-MDA-6789. Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. 40) were amide or urea analogs such as RO6870810 (TEN-010), birabresib (OTX015, MK-8628), CPI-0610 137, and BAY-1238097 (Fig. Constellation is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in a second-line setting in patients with MF who are refractory to or intolerant of or have relapsed or lost response to ruxolitinib. Participation eligibility. TEN-010 (5), 36. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in patients with myelofibrosis (MF). CPI-0610 is a potent and selective small molecule designed to promote anti-tumor activity by selectively inhibiting the function of BET proteins to decrease the expression of. The MANIFEST trial investigating this drug had 3 arms; the second arm combined ruxolitinib. CPI-0610 is a novel small-molecule bromodomain and extra terminal protein (BET) inhibitor used in patients with relapsed or refractory disease. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). Plain language summary Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). The utilization of pelabresib (CPI-0610) monotherapy demonstrated signals of clinical activity in the form of spleen volume reduction, symptom reduction, and hemoglobin benefit in patients with. About CPI-0610. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. A total of 41 patients were enrolled, of which 40 patients. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCAMBRIDGE, Mass. Store lyophilized at -20ºC, keep desiccated. The novel BET inhibitor CPI-0610 demonstrated clinical activity with or without ruxolitinib (Jakafi) in patients with JAK inhibitor-naïve and JAK inhibitor-exposed or -intolerant myelofibrosis. Treatment with a therapeutic antibody less than 4 weeks before the first. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. Molecular Weight. ” The data were gathered from 44 patients. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. The company is currently. 5% rate of reduction in spleen volume of at least 35%. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). CPI-0610. The results provide evidence of synergy between CPI-0610 and rux in these myelofibrosis patients, and the spleen and symptom benefits are. CPI-0610 was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients. Finally, in Arm 3, which looked at CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve patients, 67% of subjects achieved a ≥35% reduction in SVR35 at the 24. Pelabresib (CPI-0610) The MANIFEST clinical trial is evaluating the role of Pelabresib (CPI-0610), a BET inhibitor in combination with Jakafi (ruxoltinib) in patients with myelofibrosis (MF). A minimum 2-week period between the last treatment with a therapeutic antibody and the. For a discussion of other risks and uncertainties, any of. For research use only. Flinn 4 , A. Constellation’s two lead product candidates, pelabresib (CPI-0610), a BET inhibitor, and CPI-0209, a second-generation EZH2 inhibitor, are in mid- to late-stage clinical trials and have broad. We look forward to the continued evaluation of CPI-0610 in this ongoing Phase 2 trial and to providing additional data from MANIFEST later this year. , Gutierrez M. Modify: 2023-11-04. We would like to show you a description here but the site won’t allow us. The combined use of pelabresib (CPI-0610) and ruxolitinib (Jakafi) demonstrated durable responses beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and in those who were JAK inhibitor naïve, according to preliminary data from arms 2 and 3 of the phase 1/2 MANIFEST trial (NCT02158858). Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. Blum 1 , J. 1. Description. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. Preclinical studies have shown that CC-90010 has significant. , Gutierrez M. 37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen. CPI-0610 is a potent and selective small molecule designed to promote anti-tumor activity by selectively inhibiting the function of BET proteins to decrease the expression of. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). Some activity was reported with CPI-0610 as a single agent in the second-line setting. com) was kept as a stock solution (10mg/ml) in DMSO (Sigma-Aldrich) and prepared and stored in. MANIFEST is an open-label Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body's normal production of blood. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. In: Clinical Lymphoma, Myeloma and Leukemia, Vol. Das (Selleck. MANIFEST is an open-label Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body's normal production of blood. . . placebo and ruxolitinib in JAK. Demonstration of efficacy and safety in these 3 arms has led to the continued development of CPI-0610. BET protein inhibition is. CPI-0610 is a selective and potent oral small molecule BETi with effects on megakaryocyte differentiation and Ck production in preclinical studies (unpublished data) and has shown antitumor activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum KA, 2018). Mascarenhas J, Kremyanskaya M, Patriarca A, Harrison C, Bose P, Rampal RK, et al. As the most extensively characterized BET protein, BRD4 has. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. and Vaswani, Rishi G. 9 Inhibiting BET may modify critical MF pathways, including. ”Mr. PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients. Constellation has aligned with the FDA on the design of MANIFEST-2, the pivotal Phase 3 clinical trial for CPI-0610 expected to begin in 2H20; Constellation plans to explore additional indications for CPI-0610; CAMBRIDGE, Mass. gov identifier: NCT02158858 ), a global, open. CPI 0610 ; View More. This study is evaluating CPI-0610 in two parts: Phase 1 Part (Complete): Open-label, sequential dose escalation study of CPI-0610 in patients with previously A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and. CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. , et al. In Arm 2, CPI-0610 is used in combination with ruxolitinib for second-line patients, and in Arm 3, CPI-0610 is used as a first-line treatment in patients who are JAKi naive, also in combination. Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in the clonal disease cells of origin in MF. Confirmation of the preliminary results in a. “Our goal is to drive CPI-0610 to registration and to transform the standard of care in myelofibrosis and potentially other hematologic diseases. gov identifier: NCT02158858 ), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients Studio di fase 3, randomizzato, in doppio cieco, con controllo attivo di CPI-0610 e Ruxolitinib rispetto a placebo e Ruxolitinib nei pazienti con MF naïve al trattamento con JAKiPhase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. 8. We are enrolling MF patients who are Janus-kinase-1/2, or JAK1/JAK2-, inhibitor-naïve, a first. ABBV-075 and JQ1 were tested. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase. Description. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. Keywords: MPN, SVR35, TSS50, ruxolitinib, fedratinib, momelotinib MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. The ProSTAR study is evaluating CPI-1205, Constellation’s potent and highly selective small-molecule EZH2 inhibitor, in combination with either enzalutamide or abiraterone / prednisone. Certain more-dramatic changes, such as incorporation of an amide isostere ( 11 ) or removal of the acetamide methylene linker ( 12 ), led to a substantial loss. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. Treatment with medications that are known to be strong inhibitors or inducers of CYP450. “Preliminary data demonstrate the potential for the combination of CPI-0610 and. FRANCESCA PALANDRI via Scopus - Elsevier. The. The CPI-0610 is a selective small molecule which promotes anti-tumor activity by inhibiting the function of BET proteins, which normally enhances target gene expression. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. For a discussion of other risks and uncertainties, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section. 1182/blood. , Maris M. Overall, the use of CPI-0610 induced a significant reduction in spleen volume of at least 35% and total symptom score reduction of at least 50%. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. CPI-0610 (pelabresib) is an oral pan BET inhibitor in clinical development []. When CPI-0610 was added to ongoing treatment with Ruxolitinib, 22% of patients achieved SVR at 24 weeks, and 34% had converted from TD, to TI. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/p. A Phase 1 Study Evaluating CPI-0610 in Patients With Previously Treated Multiple Myeloma - Full Text View. CPI-0610 is a potent and selective small molecule designed to promote anti-tumor activity by selectively inhibiting the function of BET proteins to decrease the expression of abnormally expressed genes in cancer. , Flinn I. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. In addition, the first dose of CPI-0610 should not occur before a period equal to or greater than 5 half-lives of the small molecule investigational agent has elapsed. Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. . Study of bb2121 in Multiple Myeloma Rochester, MN Study CRB-401 is a 2-part, non-randomized, open label, multi-site Phase 1 study of bb2121 in adults with relapsed/refractory multiple myeloma (MM). 39), all of which have undergone phase I. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in. , Goy A. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. Constellation developed pelabresib (CPI-0610) which inhibits members of the BET family of chromosome-binding. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). Pelabresib (CPI-0610) Catalog No. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Guidelines differ from study to study, and identify who can or cannot participate. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. Goy 5 , J. W. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Pelabresib Anhydrous is the anhydrous form of pelabresib, a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Ann Oncol. A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). CPI-1205, CPI-0610, CPI-0209, and other product candidates are investigational in nature and have not yet been approved by the FDA or other regulatory authorities. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. Figure 2. The study. 1491. (Nasdaq: CNST), a clinical-stage. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. 3 weeks in the monotherapy arm and 25. Most BET inhibitors in the clinic, including GSK525762, CPI-0610, OTX-015, and MT1, have similar structures as JQ1 and exhibited good preliminary effects on. Mertz 6 , R. Certain more-dramatic changes, such as incorporation of an amide isostere ( 11 ) or removal of the acetamide methylene linker ( 12 ), led to a substantial. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in patients with myelofibrosis (MF). PELA combined with ruxolitinib (RUX) has shown a 56% response rate for ≥50% reduction in total symptom score (TSS) at Wk 24 from baseline (BL; TSS50) in Janus kinase inhibitor. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Modify: 2023-11-04. In Arm 2, which examined CPI-0610 in combination with ruxolitinib in ruxolitinib-experienced patients, 29% of evaluable non-TD subjects achieved SVR35 at 24 weeks. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. CPI-0610 is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF. The body weights of the. 8 g/mol. For a discussion of other risks and uncertainties, any of. Context CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic. The benefits yielded with the BET inhibitor pelabresib (formerly CPI-0610) in patients with myelofibrosis are multifold, and the agent’s potential to improve disease biology and overcome. 2217/epi-2019. 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)Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical. Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. Kremyanskaya M, Mascarenhas J, Palandri F, et al. Data published in two abstracts suggest that CPI-0610 may have potential disease-modifying effects in treating myelofibrosis ; All ten evaluable patients experienced spleen volume reductions ; Improvements in symptom scores, bone marrow fibrosis, and hemoglobin levels also seen ; Two transfusion dependent patients became transfusion. Here we present results from MANIFEST. CPI-0610 is a potent, selective, and cell-active BET inhibitor. In Arm 2, CPI-0610 is used in combination with ruxolitinib for second-line patients, and in Arm 3, CPI-0610 is used as a first-line treatment in patients who are JAKi naive, also in combination. Maximal effects were observed 2 hours after treatment. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. JAKi are currently approved for treatment of MF, including ruxolitinib. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/p. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). The first study (poster #420) enrolled 32 patients with B-cell lymphoma and assigned them to oral CPI-1205 twice daily in 28-day cycles. With 63 myelofibrosis patients now treated and evaluable in the company’s mid-stage study, the 24-week spleen response rate to its oral drug, CPI-0610 — when used on top of Jakafi, Incyte’s. Two abstracts with preliminary data from the MANIFEST clinical trial from 59 enrolled patients as of June 27, 2019, the data cutoff date, were published today in association with ASH. Here we present results from MANIFEST. , May 14, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. Pelabresib (CPI-0610) Selective benzoisoxaoloazepine BET bromodomain inhibitor for BRD4-BD1 : NSD3 NSD3: AZD 5153 6-hydroxy 2-naphthoic acid ZEN-3694: Orally available BET-BRD4 bromodomain inhibitor Orally available pan-BET bromodomain inhibitor : Open in a separate window. 17, 2019. The novel targeted agent CPI-0610 enhanced responses to ruxolitinib in patients with myelofibrosis enrolled in the global phase II MANIFEST-2 trial, investigators reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition. Pelabresib (CPI-0610) is a first-in-class, oral, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of bromodomain and extraterminal domain (BET) proteins, which regulate gene expression pathways. The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225. Cross-trial comparisons with JAKi monotherapy have limitations due to. Pelabresib (CPI-0610) is an investigational selective small-molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). S7853. The isoxazole derivative CPI-0610, which exhibits an IC 50 of 120 nM for BRD4 in the MV4-11 xenograft tumour model [96, 100], was developed by Constellation Pharmaceuticals. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. 18 μM for MYC [1] . clinicaltrials. Nov 2022;CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients Patients treated with CPI-0610 exhibited improvement in spleen volume, constitutional symptoms, anemia, bone marrow fibrosis, and transfusion dependenceA potent, oral small-molecule bromodomain and extraterminal domain (BET) inhibitor—CPI-0610—improves spleen volume and symptoms when added to the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) in ruxolitinib-naïve patients with myelofibrosis. e. D, A STRING network, which is used to model known or predicted protein–protein interactions from custom gene lists, was seeded with significant hits from both the CPI-0610 and JQ1 CRISPR screens, and identifies a concordant network of enriched hits of interest across both JQ1 and CPI-0610 CRISPR screens centered on hematopoietic TFs, AHR, and. MOR210/TJ210/HIB210 is a human antibody directed against C5aR1, the receptor of the complement factor C5a, currently in Phase 1 clinical development. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. CPI-1205, CPI-0610, CPI-0209, and other product candidates are investigational in nature and have not yet been approved by the FDA or other regulatory authorities. Constellation Pharmaceuticals was a clinical-stage biopharmaceutical company developing novel therapeutics that selectively modulate gene expression to address serious unmet medical needs in patients with cancer. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. Go to. Abramson J. ” Data Highlights . 2f), supporting the potential for BETi to be used for ovarian cancer. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Contact Ronald AldridgeJohn O. Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. , Aug. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. CPI-0209, a second-generation enhancer of zeste homolog 2 (EZH2) inhibitor, in Phase 2 development for hematological malignancies and solid tumors by Constellation. gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. If these preliminary data are confirmed in further testing, CPI-0610 may have the potential for disease modification and could become part of a new standard of care in myelofibrosis. A. Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. In addition, the experimental BET inhibitor CPI-0610 demonstrated an exceptional response (SPM score 97. CPI-0610 is a highly promising Phase 3 product candidate with the potential to address unmet medical needs that have been identified by both patients and physicians. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. However, the thrombocytopenia was reversible and not cumulative. 5,6 Analysis of. 2022, p. CPI-0610 monotherapy arm (n = 36): patients no longer on rux with resistant/refractory or intolerant MF and Dynamic International Prognostic Scoring System (DIPSS) ≥ intermediate; CPI-0610 starting dose at 125 mg once daily on days 1-14 (21-day dosing cycles). Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. CPI-0610 treatment resulted in MM cytotoxicity in vitro by inducing G 1 cell cycle arrest and caspase-dependent apoptosis. CPI-0610 will be administered 200mg orally once a daily for 14 consecutive days followed by a 7-day break. 1,2 “Preliminary data demonstrate the. / Mascarenhas, John; Kremyanskaya, Marina; Patriarca, Andrea et al. Although CPI-0610 was tested at doses as high as. The combined use of pelabresib (CPI-0610) and ruxolitinib (Jakafi) demonstrated durable responses beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and. About CPI-0610. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. Products with only one mechanism of action are approved. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. In the study, CPI-0610 is being investigated as an add-on to ruxolitinib in patients with advanced myelofibrosis who have experienced a suboptimal response to ruxolitinib as a single agent. Background: Pelabresib (CPI-0610), an investigational product, in combination with ruxolitinib (ruxo) has shown encouraging responses in terms of ≥35% reduction in spleen volume from baseline (SVR35) and ≥50% reduction in total symptoms score (TSS) from baseline (TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients with. e. 9% median reduction in spleen volume at 24 weeks and a 58. CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; The effect of CPI-0610 on the viability of MM cell lines and primary MM cells was determined by measuring MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Chemicon International. Scandura, MD, PhD, reflected on its potential role for patients with myelofibrosis and studies evaluating. The Phase 1 portion of the CPI-0209 Phase1/2 clinical trial is an open label, dose escalation study in patients with advanced tumors. Overall, the use of. cpi-0610 Data presented at ASCO and EHA from the MANIFEST study suggest that CPI-0610 may have disease-modifying effects. Kremyanskaya, M, Mascarenhas J, Palandri F, et al. 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. Treatment with JAK inhibitor (JAKi) ruxolitinib (rux) or fedratinib. Initial studies indicated that CPI-0610 offers some improvement in terms of selectivity for (i) BRD4 (2-fold over other BET family members), and (ii) between BRD4. (B) Comparison of average IC 50 s of BET inhibitors from patient-derived samples. BET inhibitors in clinical development (ABBV-075, I-BET762, CPI-0610) are variably effective in limiting CTCL cell viability (A) Representative dose-response curves of CTCL cells derived from patient 11 to different BET inhibitors. Data published in two abstracts suggest that CPI-0610 may have potential disease-modifying effects in treating myelofibrosis ; All ten evaluable patients experienced spleen volume reductions ; Improvements in symptom scores, bone marrow fibrosis, and hemoglobin levels also seen ; Two transfusion dependent patients became transfusion. Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). CPI-0610 treatment of CD34+ cells from MF patients in MK differentiating conditions in the presence of SCF, IL6, IL9 and TPO resulted in a dose-dependent. “There is a dose-dependent and concentration-dependent inhibition of IL8 and CCR1, and both are NF-kB dependent genes,” Senderowicz said. In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. Over the past decade, numerous pan-BET inhibitors have been generated, and some of them are currently in clinical trials, such as OTX-015, CPI-0610, and I-BET762. There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; CAMBRIDGE, Mass. When CPI-0610 was added to ongoing treatment with Ruxolitinib, 22% of patients achieved SVR at 24 weeks, and 34% had converted from TD, to TI. Single agent CPI-0610 treatment also significantly decreased tumour weight by 42% when compared to vehicle (Fig. Drug selectivity of BRD4 small-molecule inhibitors. These are phase three studies that are planned to start soon for possible approval for combinations over JAK inhibitor alone for different problems that people face. 8 of 21 (38%. Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT. ” Data Highlights . 11 is a potent selective inhibitor of BET proteins, which inhibits BRD4 BD1 with IC 50 of 39 nM in TR-FRET (time-resolved fluorescence energy transfer) assay, and exhibits anti-tumor. Although CPI-0610 was tested at doses as high as 400 mg PO QD, the maximum tolerated dose was 225 mg PO QD for 2 weeks on, 1 week off. Both the CPI-0610 and navitoclax combinations with ruxolitinib are also being studied in the JAK inhibitor-naïve setting; early results with the former are promising (10 of 15 (66. Importantly, CC-90010 has a longer terminal half-life [∼60 h (±15% CV)] for the RP2D than other BET. 2015; 126:1491. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow. 2020-04-14. gov identifier: NCT02158858 ), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. 1 (PubChem release 2021. UPDATE: Constar Intl (CNST) Reports Update on MANIFEST Clinical Trial of CPI-0610 in Myelofibrosis Article Related Press Releases ( 1 ) Stock Quotes (1) Comments (0) FREE Breaking News Alerts from. Clear anti-tumor activity was observed in. The. METHODS MANIFEST (ClinicalTrails. This CPI-0610-induced dose-dependent maturation of aberrant immature MK cells may play a role in reducing MF disease manifestations. Nonetheless, five patients showed objective response, which included two complete responses (CRs) and three PRs; five patients had prolonged (>6 months) SD, indicating that CPI-0610 was a well-tolerated drug with clinical activity in patients with advanced. MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. The rate of 63% was still a good response for this therapy since, in similar patient populations, the response rate is usually about 50% to 60%. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. CPI-0610 demonstrated activity, both as a monotherapy and as add on to ruxolitinib, in second-line or later settings; Translational data supports potential disease-modifying effects of CPI-0610; CAMBRIDGE, Mass. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. The combination was well-tolerated. , Goy A. doi: 10. A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. Like ruxolitinib failure, there is also no uniformly accepted. 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated.