Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. 63 KB ; Poster Updated Durability of Response and Safety in MANIFEST Arm 3: Pelabresib (CPI-0610) Combined With Ruxolitinib for JAK Inhibitor Treatment-Naïve. 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. 5,6 Analysis of. Data from pacritinib in the first line setting, seen here, cannot be compared to any arm of the MANIFEST trial. An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that. . Cross-trial comparisons with JAKi monotherapy have limitations due to. 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. A phase I study of Cpi-0610, a Bromodomain And Extra Terminal Protein (BET) inhibitor in patients with relapsed or refractory lymphoma. Patients tolerated CPI-0610 well; thrombocytopenia was the only overlapping toxicity with ruxolitinib but was non-cumulative and reversible. 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. doi: 10. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Menu icon A vertical stack of three evenly. 31 Pharmacokinetic parameters were dose-proportional for the evaluated doses. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect. 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. CPI-0610 7. 3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84). This study is sponsored by Constellation Pharmaceuticals a MorphoSys Company. 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). 2020-04-14. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. 21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeksCAMBRIDGE, Mass. Furthermore, in a Phase 1 clinical trial of CPI-0610, the Company also showed that the dose-limiting toxicity of thrombocytopenia was reversible and non-cumulative. Contact Ronald Aldridge Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). 41O A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma K. Delaney has a track. This study is exploring either CPI-0610 alone or in combination with ruxolitinib (Janus kinase 1/2 inhibitor). 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). Your purchase entitles you to full access to the information. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 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. BET inhibitors combined with other drugs may have better prospects. 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. – Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –– Expands study to include an additio. Article. 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). A. 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. 8. 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. , et al. Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. While CPI-0610, Nil, and the combination significantly reduced spleen size , only the combination significantly reduced donor leukaemic CD45. Mascarenhas J, Harrison C, Luptakova K, et al. 17, 2019. Maris 3 , I. Pelabresib - MorphoSys. Open in a separate window. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). 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. Collectively, these data indicate that CPI-0610 +/- RUX might. gov NCT No: NCT02158858 Opens a new window. 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 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. 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. 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. 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. 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. “Our goal is to drive CPI-0610 to registration and to transform the standard of care in myelofibrosis and potentially other hematologic diseases. The study. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxoliti. 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. There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. Treatment with medications that are known to be strong inhibitors or inducers of CYP450. 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. The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on. , Goy A. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. BET proteins are known to promote cancer growth. CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). Although CPI-0610 was tested at doses as high as. JAKi are currently approved for treatment of MF, including ruxolitinib. 2019 Nov;11(14):1553-1555. For research use only. 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. [Google Scholar]In addition, the Company is amending the design of MANIFEST to include a third cohort designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/. , Maris M. The combination was well-tolerated. Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total. Abstract. (C)-JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610 chemical structures are shown. 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. CPI-0610 is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF. Store lyophilized at -20ºC, keep desiccated. Clear anti-tumor activity was observed in. gov identifier: NCT02158858 ), a global, open. METHODS MANIFEST (ClinicalTrails. 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. The 14 days of CPI-0610 dosing and the 7-day break together constitute 1 cycle of treatment. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Mascarenhas J, Kremyanskaya M, Patriarca A, Harrison C, Bose P, Rampal RK, et al. This CPI-0610-induced dose-dependent maturation of aberrant immature MK cells may play a role in reducing MF disease manifestations. 1 (PubChem release 2021. Mascarenhas J, Harrison C, Luptakova K, et al. 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). W. CPI-0610. 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. Interim data from this study have shown promising results,. Mertz 6 , R. and ABBV-07 5 (6). BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular. CPI-0610 data was 29% and 38%, which also compares favorably with the above data. We plan to provide a further update on CPI-0610 in oral and poster presentations and at an investor event at the ASH meeting on December 9. 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. ”Mr. About CPI-0610. Like ruxolitinib failure, there is also no uniformly accepted. CPI-0610 induces apoptosis and G 1 cell cycle arrest associated with MYC downregulation. 18 μM for MYC. Of the 54 patients treated with CPI-0610 and ruxolitinib, 41 were still receiving the combination at that time. Products with only one mechanism of action are approved. CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded. When. 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. W. 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; Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). doi: 10. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). 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. 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. Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. Abstract. Ruxolitinib is the only FDA-approved treatment for myelofibrosis. , Goy A. 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. Modify: 2023-11-04. . Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1,. Preclinical studies have shown that CC-90010 has significant. CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G 1 cell cycle arrest and caspase-dependent apoptosis. Blood. 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. 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. 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 (pelabresib) is an oral pan BET inhibitor in clinical development []. Pelabresib (CPI-0610) in Myelofibrosis: Pelabresib is an oral small-molecule BET inhibitor currently under investigation for the treatment of MF. 2 + cells in the bone marrow (protected by the niche. 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 potent, selective and unique BET inhibitor under investigation in MF patients as monotherapy or in combination with ruxolitinib in the MANIFEST trial (NCT02158858). MANIFEST-2: CPI-0610 Shows Benefit in Myelofibrosis. 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. 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. The primary endpoint of each trial was to establish the safety of CPI-0610 as a single agent by evaluating the frequency of dose-limiting toxicities associated with treatment with CPI-0610 for 21 days. Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients. The company is currently. [1] [2] [3] [4] Abstract. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. It has potential applications in the treatment of various forms of cancer . Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Like ruxolitinib failure, there is also no uniformly accepted. CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. . CPI-0610 significantly delayed tumor growth and increased theCPI-0610 is an effective BET inhibitor in multiple myeloma (MM) and is currently being tested in phase I clinical trial [84]. CPI-0610, is an oral inhibitor of bromodomain and extraterminal domain (BET) proteins that inhibits cytokine production and promotes megakaryocytic and erythroid differentiation. Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. 8. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. For a discussion of other risks and uncertainties, any 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. Computed by PubChem 2. cpi-0610 Data presented at ASCO and EHA from the MANIFEST study suggest that CPI-0610 may have disease-modifying effects. BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow. their clin ical invest igation s are focused on cancer therapies. Buy Profile. 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 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). CPI-0610, CPI-1205 and CPI-0209 are investigational therapies and have not been approved by the FDA (or any other regulatory authority). 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. 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. gov, NCT04603495) trial, which will evaluate the efficacy and safety of pelabresib (CPI-0610) and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. placebo and ruxolitinib in JAK. 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. , May 14, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. 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. BET protein inhibition is. e. To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1. Recent. ” The data were gathered from 44 patients. 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 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. 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. Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. The two patients. HemaSphere 2022;6:99-100). “There is a dose-dependent and concentration-dependent inhibition of IL8 and CCR1, and both are NF-kB dependent genes,” Senderowicz said. Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis. (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. @article{osti_1855473, title = {Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal}, author = {Albrecht, Brian K. ” The data were gathered from 44 patients. 35, 40, 41 In addition, CPI-0610, PLX51107, and INCB0543294 belong to isoxazole-based BRD4 inhibitors. Pelabresib (CPI-0610) is an investigational, oral, small-molecule bromodomain and extraterminal (BET) domain inhibitor. The first-generation BET bromodomain inhibitors tested in the clinic, including GSK525762 (I-BET762), OTX-015, and CPI-0610, are thienotriazolodiazepine or benzodiazepine compounds and have. RVX2135, FT-1101, BAY1238097. Here we present results from MANIFEST. 40) were amide or urea analogs such as RO6870810 (TEN-010), birabresib (OTX015, MK-8628), CPI-0610 137, and BAY-1238097 (Fig. 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. 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). Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients - AdisInsightA 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). The BET inhibitor CPI-0610 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. 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. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing phase 1 study. I-BET151 showed beneficial effects in the treatment of GBM and leukemia. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. 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). Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients. 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. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. We are currently conducting MANIFEST, a Phase 2 clinical trial of CPI-0610 as a monotherapy and in combination with ruxolitinib (marketed as Jakafi ® /Jakavi ®) in patients with myelofibrosis, or MF, a progressive hematological cancer. Adis is an information provider. 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. 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. 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. According to Mayo Clinic, “Myelofibrosis is an uncommon type of. About CPI-0610. 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. For a discussion of other risks and uncertainties, any of. V126. S7853. METHODS MANIFEST (ClinicalTrails. We would like to show you a description here but the site won’t allow us. 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. 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. CPI-0610 (0-1500 nM; 72 hours; Multiple myeloma cell lines and primary MM cells) treatment reduces the viability of MM cells in a dose-dependent manner [2]. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). 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. There is no guarantee that. 2217/epi-2019. S. 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. 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. 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. Scandura, MD, PhD, reflected on its potential role for patients with myelofibrosis and studies evaluating. 37. 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. Doses of 170 and 230 mg QD are associated with a 50% average. 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. 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. Guidelines differ from study to study, and identify who can or cannot participate. We previously evaluated CPI-0610 in three Phase 1 clinical trials in an aggregate of 138 patients with hematological malignancies. 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. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with. 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. 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. and Cote, Alexandre and Leblanc, Yves and Nasveschuk, Christopher G. Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, has the 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 myelofibrosis (MF). Table 3 lists three such trials, early results from which have been presented. Figure 2. . These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of. For a discussion of other risks and uncertainties, any of. Here we present results from MANIFEST. As previously reported at ASH 2020, 42 of 63 evaluable patients (67%) achieved a ≥35%. JAKi are currently approved for treatment of MF, including ruxolitinib. In one of. As the inhibition of individual BET bromodomains will lead to different. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. 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. Contact Ronald AldridgePelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). 39), all of which have undergone phase I. 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. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. and Hewitt, Michael C. We would like to show you a description here but the site won’t allow us. Das (Selleck. PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-TREATMENT-NAIVE MYELOFIBROSIS PATIENTS. Optional tumor biopsy will be obtained prior to Day 1 of CPI-0610 administration. 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. It has potential applications in the treatment of various forms of cancer . A Phase 1 Study Evaluating CPI-0610 in Patients With Previously Treated Multiple Myeloma - Full Text View. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. CPI 0610 ; View More. 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). In addition, the experimental BET inhibitor CPI-0610 demonstrated an exceptional response (SPM score 97. 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. Spleen response rates in first-line patients at 12 weeks and 24 weeks in line with previously. 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. CPI-203 and CPI-0610 were obtained from Constellation Pharmaceuticals and kept as a solid powder at room temperature (RT). Sims 6 , F. 1182/blood. The CPI-0610 starting daily dose was 125 mg, 2 weeks on, 2 weeks off. Pelabresib (CPI-0610) is a synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical. 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. chem. 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 drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24. For example, patients experienced immune responses, improvements in quality of life, and an occasional. 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. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. 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. Background: CPI-0610, a selective and potent small molecule BETi, has shown clinical activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum KA, 2018). Alternative Names: CPI-0610. Keywords: CPI-0610 •JAKitreatment-naive MANIFEST-2 myelofibrosis pelabresib ruxolitinib Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) that includes primary MF as well as MF that develops after a diagnosis of polycythemia vera or essential thrombocythemia [1,2]. In the MANIFEST-2 phase 3 study, CPI-0610 plus ruxolitinib will be compared to placebo plus ruxolitinib in JAK inhibitor–naïve MF patients with at least DIPSS intermediate-1 disease, splenomegaly by imaging, and symptomatic MF. 05. 6%) evaluable patients achieved ≥50% TSS reduction at 24 weeks) 92 and a randomized phase 3 trial of. 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. Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients. 45 Although small-molecule pan-BET inhibitors show promising effects in clinical evaluation, there are still problems and challenges to overcome, such as the moderate clinical. 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. 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. 9%. The benzoisoxazoloazepine CPI-0610 decreased MYC transcripts in vivo and reduced leukemia xenograft tumor growth, which was synergistic with doxorubicin treatment [117]. 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. (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. About CPI-0610. 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. 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). CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Flinn 4 , A. 05, 2020 (GLOBE NEWSWIRE) -- Constellation Pharmaceuticals, Inc. Molecular Weight. Abramson JS, Blum KA, Flinn IW, et al. 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. CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Dose increase by 25 mg was allowed from Cycle 3 onwards to a maximum dose of 225 mgThe combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) produced responses that proved to be durable beyond week 24 in patients with myelofibrosis who experienced a suboptimal response. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. 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. Pelabresib (previously CPI-0610) is a first-in-class, selective, oral small-molecule BET proteins inhibitor. Description. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225. Ruxolitinib (marketed as Jakafi) is the standard of care treatment for patients with. Blum 1 , J. 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. Price : $50 *. 2217/epi-2019-0274. , Gutierrez M. Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis. Confirmation of the preliminary results in a. 此外，在黑色素瘤中，PLX51107可降低PD-L1的表达水平，同时调节免疫细胞和肿瘤微环境[52]。CPI-0610在骨髓纤维化患者中，通过抑制Brd4降低Nf-κb的表达水平，从而抑制IL-8等促炎细胞因子的产生。Another BET inhibitor, CPI-0610, demonstrated ≥50% suppression of CCR1 at 6 h post-dose, which correlated with the clinical response in patients with R/R lymphoma. MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF CPI 0610 AND RUXOLITINIB VS. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. 1,2. 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. For a discussion of other risks and uncertainties, any of. Clear anti-tumor activity was observed in. CPI-0610 is being studied in multiple different ways. Constellation’s epigenetics platform includes a deep understanding of the biological contexts in which BET proteins operate. , 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. For a discussion of other risks and uncertainties, any of. ” Data Highlights . CPI-0610 has been well tolerated, with the principal toxicity being dose-dependent thrombocytopenia that is reversible and non-cumulative. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients. The two patients treated with a combination of CPI-0610 and ruxolitinib (i. The future of epigenetic therapy: CPI-0610 for the treatment of myeloidfibrosis Epigenomics. CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. 2 of 10 (20%) and 4 of 11 (36%) evaluable non-transfusion-dependent (non-TD) patients achieved SVR35 (the. The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells. We would like to show you a description here but the site won’t allow us. Single agent CPI-0610 treatment also significantly decreased tumour weight by 42% when compared to vehicle (Fig. Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Abramson 2 , M. 18 μM for MYC. 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. 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. Constellation Pharmaceuticals Provides Updates of MANIFEST Study for CPI-0610 and EZH2 Franchise. CPI-0610 inhibits BRD4-BD1 with an IC50 of 39 nM, and with an EC50 value of 0. - Mechanism of Action & Protocol. Drug selectivity of BRD4 small-molecule inhibitors. 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. The dose will not be adjusted for body weight or. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in. As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). In lyophilized form, the chemical is stable for 36 months. Maximal effects were observed 2 hours after treatment. 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 synthetic, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of BET proteins currently in clinical development. 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). 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. , 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. (Nasdaq: CNST), a clinical-stage. 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. Haematologica. 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. However, the thrombocytopenia was reversible and not cumulative. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. 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. A. Ruxolitinib is the only FDA-approved treatment for 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. MANIFEST TrialCPI-0610 (4), 35. Browse Publications Technical Papers 2020-01-0610.