CPI-0610 is a potent, selective, and cell-active BET inhibitor. , CPI-0610 added onto existing treatment with ruxolitinib) have been treated for over 16 months. In patients with MF, the bone marrow becomes overactive, leading to scarring and. 2 + cells in the bone marrow (protected by the niche. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. 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 a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. 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. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. Most of. PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. 5% rate of reduction in spleen volume of at least 35%. Ruxolitinib (marketed as Jakafi) is the standard of care treatment for patients with. V126. 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. 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. , May 14, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. In one of. Modify: 2023-11-04. Authors Jigar Raythatha 1 , Lauren Arnold 1 Affiliation 1 Constellation Pharmaceuticals. 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. 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. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) 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 MF. CPI-0610 can become a part of the standard of care and even expand the overall addressable market in myelofibrosis indication. Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET). Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. 2f), supporting the potential for BETi to be used for ovarian cancer. 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). CPI0610, CPI-0610. CPI-0610 is being studied in multiple different ways. MANIFEST-2: CPI-0610 Shows Benefit in Myelofibrosis. CPI-0610 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. This Phase 3, randomized, blinded study is comparing CPI-0610 and ruxolitinib with placebo and ruxolitinib in JAKi treatment-naive patients with primary A Phase 3, Randomized, Double-blind, Active-Control Study of Pelabresib (CPI-0610) and Ruxolitinib vs. 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. Pelabresib (CPI-0610) Catalog No. , Goy A. About CPI-0610. 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%. Buy Profile. ” The data were gathered from 44 patients. Pelabresib (CPI-0610) Monotherapy in Patients With High-Risk Essential Thrombocythemia Refractory or Intolerant to Hydroxyurea: Preliminary Results From MANIFEST Study pdf | 552. The abstracts include. 2217/epi-2019-0274. 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). (Nasdaq: CNST) today announced that two oral. 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. The MANIFEST trial investigating this drug had 3 arms; the second arm combined ruxolitinib. Additionally, we have begun planning for a randomized. 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%. 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. CPI-0610 and CPI-1205 are each in Phase 2 clinical trials, and a third program, CPI-0209, is expected to begin a Phase 1 clinical trial in mid-2019. The combination was well-tolerated. MANIFEST Trial of CPI-0610. Phase 1 Part (Complete): Open-label, sequential dose escalation study of pelabresib in patients with previously treated Acute Leukemia, Myelodysplastic. Strategic Funding PartnershipCPI-0610 (Constellation Pharmaceuticals, Cambridge, MA) is a potent, orally bioavailable inhibitor of BET proteins that is being studied in different clinical scenarios (as a single agent after ruxolitinib, as an “add-on” therapy to ruxolitinib and in combination with ruxolitinib in JAK inhibitor naïve patients with MF) in the ongoing. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously reported data and differentiated from standard of careSpleen responses demonstrated. Open in a separate window. Context: Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk. Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. . Of the 54 patients treated with CPI-0610 and ruxolitinib, 41 were still receiving the combination at that time. Double-blind treatment (CPI-0610 or matching placebo) will be administered daily for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 days). Article. 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. [1] [2]. 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. 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. 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;CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. 18 μM for MYC. Patients in the two second-line arms are being stratified based on transfusion dependent status. 35. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. Constellation’s epigenetics platform includes a deep understanding of the biological contexts in which BET proteins operate. . 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. Methods: MANIFEST (ClinicalTrails. (C)-JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610 chemical structures are shown. Your purchase entitles you to full access to the information. Constellation is driving development of the BET inhibitor pelabresib (CPI-0610) for the treatment of myelofibrosis as well as its EZH2 inhibitor CPI-0209 for the treatment of other cancers. With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. The company is currently. METHODS MANIFEST (ClinicalTrails. Methods: MANIFEST (ClinicalTrails. Phone Number: 1-877-MDA-6789. Masarova says that CPI-0610, a bromodomain, and extra-terminal (BET) inhibitor holds promise in patients with myelofibrosis since it could alter the transcription factors and potentially overcome the patient’s resistance to ruxolitinib (Jakafi). 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. In a phase II trial of CPI-0610 added to ruxolitinib, 63% of patients with no prior JAK inhibitor treatment had at least a 35% reduction in spleen volume (SVR35, the primary endpoint) and an. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. Haematologica. 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, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. gov NCT No: NCT02158858 Opens a new window. 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. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. 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. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). Cross-trial comparisons with JAKi monotherapy have limitations due to. 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. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical development. 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. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. 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). S7853. JAKi are currently approved for treatment of MF, including ruxolitinib. “Preliminary data demonstrate the potential for the combination of CPI-0610 and. Upon administration, pelabresib binds to the acetylated lysine recognition motifs on the bromodomain of BET. 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. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. . CPI-0610 is a drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. 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. 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). We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. CPI-0610 and CPI-1205 are each in Phase 2 clinical trials, and a third program, CPI-0209, is expected to begin a Phase 1 clinical trial in mid-2019. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. , Maris M. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. We are enrolling MF patients who are Janus-kinase-1/2, or JAK1/JAK2-, inhibitor-naïve, a first. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Delaney has a track. Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1,. Kremyanskaya M, Mascarenhas J, Palandri F, et al. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. A phase 1 study evaluating CPI-0610 in patients with progressive lymphoma: NHL or Hodgkin's lymphoma: Secondary outcome: Changes in the expression of MYC and other genes in tumor tissue: Phase 2 NCT02674750: Study to evaluate the efficacy and safety of CUDC-907 in patients with RR DLBCL, including patients with MYC alterationsFor this reason, the compounds that reached clinical trials (Fig. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. Treatment with a therapeutic antibody less than 4 weeks before the first. 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. However, toxicity studies. 1,2 “Preliminary data demonstrate the. The dose will not be adjusted for body weight or. 39), all of which have undergone phase I. ” The data were gathered from 44 patients. ABBV-075 and JQ1 were tested. 06, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. , Dec. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. Pelabresib (CPI-0610) is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor with an IC50 of 39 nM for BRD4-BD1 in TR-FRET assay and currently undergoing human clinical trials for hematological malignancies. 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. 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. Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). CPI-0610 is a potent, selective, and cell-active BET inhibitor. In the phase II MANIFEST study, Pelabresib is being evaluated as monotherapy and in combination with the JAK inhibitor ruxolitinib. 9 weeks in the combination arm. An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that. CPI-0610 showed signals of clinical activity, both as a monotherapy and in combination with ruxolitinib, in refractory myelofibrosis (MF) patients. In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 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. Between September 2013 and March 2015 44 patients had been enrolled and treated at doses of 6, 12, 24, 48, 80, 120, 170. Royalty Pharma will purchase the rights to receive 3% of future net sales of CPI-0209. Substitution on the amide nitrogen was not required for potency, as illustrated by 10 (CPI-0610), which also demonstrated greater in vitro metabolic stability than the secondary amides. 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. The recommended Phase 2 dose of CPI-0610 in the MANIFEST study is 125 mg once daily (may be titrated up), which is below the maximum tolerated dose of 225 mg once daily. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). Here we describe the rationale and design for the phase III MANIFEST-2 (ClinicalTrials. Adis is an information provider. 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. In lyophilized form, the chemical is stable for 36 months. 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. Context: Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk myelofibrosis in Arm 3 of the Phase 2 MANIFEST study (NCT02158858). CPI-0610 data was 29% and 38%, which also compares favorably with the above data. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. 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) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB gene expression and other relevant genes involved in MF disease pathways. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. CPI-0610 is a potent, selective and unique BET inhibitor under investigation in MF patients as monotherapy or in combination with ruxolitinib in the MANIFEST trial (NCT02158858). However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. Brief Summary: A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in. The study. clinicaltrials. 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. The Phase 1 portion of the CPI-0209 Phase1/2 clinical trial is an open label, dose escalation study in patients with advanced tumors. An additional cohort is recruiting JAKi naïve patients to receive CPI-0610/ruxolitinib combination, and showed encouraging preliminary activity [33]. METHODS. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. It is designed to downregulate BET target genes and modify nuclear factor kappa B. placebo and ruxolitinib in JAK. Pelabresib is being investigated as a treatment for myelofibrosis and has not. CPI-0610 is a drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. 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). 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. 9% median reduction in spleen volume at 24 weeks and a 58. 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. MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis – JAK Inhibitor-Naïe or With Suboptimal Response to Ruxolitinib – Preliminary Data From the MANIFEST Study. CPI-0610-mediated BET. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. MANIFEST TrialCPI-0610 (4), 35. 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 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Download scientific diagram | BET bromodomain inhibitor molecules. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. 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. 7%) evaluable patients achieved ≥35% SVR and 11 of 14 (78. ” Data HighlightsCPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 1 (PubChem release 2021. 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. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. , Maris M. Continued high rate of SVR35 in 1L patients: 72% at 12 weeks and 67% at 24 weeksSVR35 responses and transfusion dependence conversion observed in. METHODS MANIFEST (ClinicalTrails. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. (Nasdaq: CNST) today announced that three abstracts relating to the MANIFEST clinical trial of CPI-0610 in myelofibrosis were published online in association with the European Hematology Association (EHA) annual meeting. Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients . Aims: Data (Sep 2021 data cut) on the safety and efficacy of pelabresib in combination with RUX in pts with MF from Arms 2 and 3 of the ongoing, open-label. ” Data Highlights . Browse Publications Technical Papers 2020-01-0610. Clear anti-tumor activity was observed in. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. Constellation is driving development of the BET inhibitor pelabresib (CPI-0610) for the treatment of myelofibrosis as well as its EZH2 inhibitor CPI-0209 for the treatment of other cancers. 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. It has potential applications in the treatment of various forms of cancer . Products with only one mechanism of action are approved. 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. MPN-375 BET inhibitor Pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis—JAK inhibitor-Naïe or with suboptimal response to ruxolitinib—preliminary data from the MANIFEST study. . CPI-0610 is a novel small-molecule bromodomain and extra terminal protein (BET) inhibitor used in patients with relapsed or refractory disease. 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. 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. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on. Maris 3 , I. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. Collectively, these data indicate that CPI-0610 +/- RUX might. Keywords: MPN, SVR35, TSS50, ruxolitinib, fedratinib, momelotinib MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. It strongly and selectively binds to the bromodomains of all four BET proteins and inhibits their interaction with acetylated lysine residues on chromatin, disrupting chromatin remodelling and gene expression [2•]. 1182/blood. 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. Treatment with medications that are known to be strong inhibitors or inducers of CYP450. ” Data Highlights . CPI-0610 is a first-in-class inhibitor of bromodomain and extraterminal domain (BET) proteins, which regulate gene transcription in numerous pro-fibrotic pathways. 18 μM for MYC. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. 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. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. 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. Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. PMID: 31729905 DOI: 10. In the monotherapy group, TD patients had a spleen volume response (SVR) of 25%, while in the non-TD group, SVR was 0%. @article{osti_1855473, title = {Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal}, author = {Albrecht, Brian K. 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 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. Products with only one mechanism of action are approved. 9%. , Flinn I. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Garner ,Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. 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). Abstract. CPI-0610 rapidly suppressed expression of both proinflammatory cytokines. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. 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. chem. placebo and ruxolitinib in JAK. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. 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. Alternative Names: CPI-0610. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. We are also exploring other novel cancer epigenetics targets in preclinical testing to fuel a sustainable pipeline of innovative small-molecule product candidates. 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. Contact Ronald AldridgeJohn O. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 37. 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. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow. , Aug. 2020-04-14. It has potential applications in the treatment of various forms of cancer . Cross-trial comparisons with JAKi monotherapy have limitations due to. 1,2. – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. 6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. For a discussion of other risks and uncertainties, any of. 5,6 Analysis of. Das (Selleck. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. In preclinical studies, pelabresib treatment results in downregulation of NF-κB signaling activity, accompanied by loss of viability in ABC- diffuse large B-cell lymphoma. 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. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) 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 MF. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Description. 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). Treatment with JAK inhibitor (JAKi) ruxolitinib (rux) or fedratinib. MOR210/TJ210/HIB210 is a human antibody directed against C5aR1, the receptor of the complement factor C5a, currently in Phase 1 clinical development. 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. These results may partially explain CPI-0610's clinical effects in MF patients, including rising hemoglobin, reduced transfusion dependency and reduction in spleen volume and symptoms. Pelabresib is currently being investigated as a treatment for myelofibrosis and. 18 μM for MYC [1] . Mascarenhas J, Harrison C, Luptakova K, et al. 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; 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. 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. Nov 2022;Constellation is driving development of the BET inhibitor CPI-0610 for the treatment of myelofibrosis as well as the EZH2 inhibitors CPI-1205 and CPI-0209 for the treatment of metastatic. Pelabresib - MorphoSys. The study evaluated CPI-0610 as a monotherapy in arm 1, as an add-on to ruxolitinib in arm 2, and in combination with ruxolitinib in the arm 3. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. 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. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged. Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. ”Mr. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G 1 cell cycle arrest and caspase-dependent apoptosis. We would like to show you a description here but the site won’t allow us. 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. 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. Strategic Funding PartnershipWe 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. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. 2015; 126:1491. Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients. Some activity was reported with CPI-0610 as a single agent in the second-line setting. BET Inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing. e. 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). Modify: 2023-11-04. 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. 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. RVX2135, FT-1101, BAY1238097. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing manifest trial. 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). CPI-0610 is a potent, selective, and cell-active BET inhibitor. 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. Study Description. CPI-0610. Pelabresib is being investigated as a treatment for myelofibrosis and has not. 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. Store lyophilized at -20ºC, keep desiccated. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and. Participation eligibility. The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification. 8% median improvement in TSS for transfusion dependent (TD. Article. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225. Mascarenhas J, Harrison C, Luptakova K, et al. 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 Poster #2568 Date: Sunday, December 12, 2021 Presentation Time: 6:00 PM - 8:00 PMCPI-0610 significantly delayed tumor growth and increased the survival of MM-bearing SCID mice. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition.