Constellation Pharmaceuticals (United States)

Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Patients (pts) can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). Bromodomain and extraterminal (BET) domain protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Aims: To present preliminary results from Arm 4 of the MANIFEST study investigating PELA monotherapy in pts with HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets >600 x 109/L and ≥2 symptoms (average score ≥3/total symptom score [TSS] ≥15 in Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF]). Pts received oral PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 109/L), white blood cell (WBC) count (≤10 x 109/L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 109/L and WBC ≤10 x 109/L), symptom improvement (≥50% reduction in MPN-SAF TSS) and safety. Pharmacodynamic biomarker assessments included genotyping, circulating cytokines and gene expression changes during treatment via peripheral blood sampling and bone marrow biopsies. Results: As of July 2022, 20 pts with HR ET received PELA; 70% (14/20) of pts were ongoing treatment, and 35% (7/20) reached 24 wks. Median age was 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 109/L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table 1). Median platelet and WBC count at Wk 12 was 446 x 109/L and 8.2 x 109/L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% of pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Baseline mutation data were available for 17 pts: JAK2V617F (8/17 pts; variant allele frequency [VAF] range 8–67%), CALR (8/17 pts; VAF range 14–27%) and MPL (1/17 pts; VAF 25%). Among the six patients with JAK2 mutation, two patients with highest JAK2 VAF showed a VAF decrease with PELA treatment (67% to 20% at end of treatment, and 52% to 40% at 24 wks). A cluster of seven cytokines (hepcidin, MMP-9, BDNF, TIMP-3, MMP-1, DKK-1 and RANTES) were downregulated post PELA at 2 wks (13/13 pts). A 65% ± SD 0.246 decrease in IL8 gene expression was also observed 4 hrs after first PELA dose (n=18), 41% ± SD 0.778 at 2 wks (n=13), and 22% ± SD 0.982 at 6 wks (n=11). Conclusion: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety data suggest a tolerable and manageable safety profile. Mutation data and other pharmacodynamic analyses indicate potential biomarker changes after PELA monotherapy.© 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved. Keywords: Myeloproliferative disorder, Essential Thrombocytemia, Inhibitor

Abstract Liquid biopsy for profiling of cell free DNA (cfDNA) in blood holds huge promise to transform how we experience and manage cancer by early detection and identification of residual disease and subtype. However, a standard blood draw yields an average of only 10 ng of cfDNA, of which DNA derived from the tumor is a small minority. Therefore, we are faced with a dilemma when utilizing the limited sample to obtain maximum information. Genetic sequencing provides information on actionable somatic mutations but detection of a few loci in a minority of the sample is challenging. Modified cytosine profiles of cancer are differential from non-cancer at many more loci and so provide a stronger signal. Moreover, they can be used to distinguish tissue-of-origin of the tumor. However, methods such as bisulfite sequencing, EM-seq and TAPS sacrifice genetic information (namely C->T mutations, which are the most common mutation in cancer) to measure modified cytosine. Genetic and modified cytosine data together have been shown to be more powerful for the detection of early cancer than either alone. Here we present a technology, which sequences at base resolution the complete genetic sequence integrated with modified cytosine from low nanogram amounts of cfDNA. It consists of (i) a single pre-sequencing workflow, which creates a copy of the original DNA and performs enzymatic base conversions which discriminate genetic and epigenetic states and (ii) post-sequencing data processing which resolves the resultant sequencing data to an information-rich 16-state code and derives genetic variants integrated with modified cytosine levels, within easy-to-use software. It is, in principle, compatible with any sequencing methodology and is shown here optimized for the Illumina fleet. In cfDNA we show accuracy of modC measurement is higher than that of bisulfite sequencing and EM-seq; and the accuracy of genetic sequencing is higher than that of Illumina alone. Accuracy of measurement is extremely important for liquid biopsy where tumor DNA is in the minority and observed in a small number of reads. We demonstrate the impact of varying base calling error rate on limit of detection for rare alleles in cfDNA samples. Further we show derivation of cfDNA fragment characteristics and that this is produced in combination with genetic and modC information. This further increases the signal available from cfDNA in only one workflow. We suggest this method will help advance the field of liquid biopsy towards its promise. Citation Format: Fabio Puddu, Casper K. Lumby, Nick Harding, David J. Morley, Jamie Scotcher, Robert Crawford, Jens Füllgrabe, Walraj S. Gosal, Shirong Yu, Daniel Brudzewsky, Jane Haywood, Andrada Tomoni, Philippa Burns, Joanna D. Holbrook, Paidi Creed. Refining liquid biopsy: generating more information from cell free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6602.

Background: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (e.g. NF-κB, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. While many MF patients (pts) receive the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) as the current standard of care, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction from BL (TSS50) are limited; thus, a significant unmet medical need exists. 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. 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 Phase 2 MANIFEST study (NCT02158858). In Arm 2, MF pts with suboptimal response to RUX are treated with pelabresib as ‘add-on’ to RUX (Arm 2A: transfusion dependent [TD]; Arm 2B: non-TD). In Arm 3, JAKi-naïve MF pts are treated with pelabresib in combination with RUX. Methods: The primary endpoints are SVR35 at Week (Wk) 24 for Arm 3 and Arm 2B (non-TD cohort) and TD to transfusion independence (TI) in Arm 2A (TD cohort). The key secondary endpoint is TSS50 per Myelofibrosis Symptom Assessment Form v4.0 at Wk 24; in Arm 2A (TD cohort), SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated. Results: At Wk 24 in Arm 3 (N=84), 68% (57/84) pts achieved SVR35 (median change: –50%; Figure), and 56% (46/82) pts achieved TSS50 (median change: –59%). Twenty-four percent of pts had a mean hemoglobin increase ≥1.5 g/dL from BL over 12 weeks without transfusions. At Wk 24 in Arm 2 (N=86), 20% (16/81) pts achieved SVR35 (median change: –18%; Figure), and 37% (30/81) pts achieved TSS50 (median change: –47%). In Arm 2A, the TD to TI rate was 16% (6/38). BM fibrosis improvement by ≥1 grade was achieved in 31% (16/52) and 25% (9/36) pts in Arm 3 and 2, respectively. Further central review and exploratory analyses of BM pathology from a more mature data set, including clinical correlations, will be presented. The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) pts in Arm 3 and 2, respectively. Anemia was reported in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) pts in Arm 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections in Arm 3 and 2 were observed but rarely a reason for treatment discontinuation. Image:Summary/Conclusion: Based on these interim Phase 2 data, pelabresib in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in splenic and symptom responses and BM fibrosis improvement, and appeared to be well tolerated. Based on data from MANIFEST Arm 3, the randomized, double-blind, active-control Phase 3 MANIFEST-2 study was initiated to further evaluate the safety and efficacy of pelabresib in combination with ruxolitinib in JAKi treatment-naïve pts with MF (NCT04603495).

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

Ophthalmic drug delivery is one of the most exciting and difficult areas of research for pharmaceutical scientists. The eye's anatomy, physiology, and biochemistry render it impenetrable to outside chemicals. The capacity to maintain a therapeutic level of the drug at the site of action for an extended period of time is a significant hurdle in ocular therapy. The ocular insert represents a substantial development in the treatment of eye illness by extending the duration of the therapeutic level of the medicine at the site of action. They are constructed of a polymeric matrix that may or may not contain a pharmaceutical agent. The medicine can then be introduced into the polymeric support as a dispersion or solution. They have a number of advantages, including increased ocular residence and prolonged pharmaceutical release into the eye. The insert is composed of a body component that is tailored to fit within the eyelid's lachrymal canaliculus. The inserts are classed as insoluble, soluble, or bioerodible based on their solubility. The drug is released from the insert by diffusion, osmosis, and bioerosion. This review aimed to provide a brief overview of Ocular Inserts – A Potential Ocular Controlled Drug Delivery Systems.