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MIR129 x MIR139 x MIR140 x MIR194 x miR-145 x miR-15a x miR-16 x miR-192	1

AbstractIntroduction:Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease where most patients relapse and have limited long-term survival. Previous studies have shown that tumor suppressor microRNA such as miR-15a plays a key role in AML and other tumor types by suppressing oncogenic targets/pathways such as BCL-2, BMI-1, WEE-1, CHK1, DCLK-1, and MCL-1. By modifying miR-15a with the cytotoxic pyrimidine 5-fluorouracil (5-FU), the 5-FU-miR-15a (CR1-02) miRNA has exhibited enhanced therapeutic efficacy, stability, as well as deliverability in multiple tumor types in pre-clinical testing.Aim:CR1-02 (EudraCT number: 2021-006332-46) is a phase I dose-escalation study evaluating the safety and tolerability of CR-001 in adults with relapsed/refractory (R/R) AML.Methods:A 3+3 study design was used with patients receiving dose levels of the synthetic double-stranded mimic of miR-15a (miRNA) (CR1-02) of 7.5 mg, 11.25 mg, 15 mg, and 18.75 mg/administration, weekly dosing. Route: administered intravenously. Excipient: GMP-grade linear polyethyleneimine (α-Methyl-ω-hydroxy-poly[(iminioethylene)chloride]; Poly[imino(1,2-ethanediyl)]; CAS Number 26913-06-4; PEI) as fixed-dose: 15 mg PEI with 7.5 mg CR1-02 and 20 mg PEI with all other dose levels of CR1-02. Biomarker data utilizing mass cytometry (CyTOF) of full blood leukocytes of peripheral blood and bone marrow was used to quantify labeled targets on the surface and interior of single cells.Results:Treatment of 11 AML patients (average age 70 y, 10 of 11 ELN2017 adverse risk) with CR1-02 was well-tolerated through 58 doses (range 1-8, average 5) administered across the 4 dose levels. The most common event was chills during the infusion, which were reduced by increasing the infusion time to two hours. One patient (NRAS VAF 48%, ASXL1 41%, TP53 23%) responded with elimination of extramedullary pericardial AML disease after 4 doses of CR1-02 but progressed in bone marrow after 8+8 doses of CR-001 (eight study doses and an additional eight doses given under compassionate use approval from the Norwegian Medicines Agency) followed by trametinib-treatment as part of another study. Five of 11 patients experienced ELN-stable disease on CR1-02. Single-cell profiling mass cytometry showed signs of molecular activity of CR1-02 on known targets of miR-15a (e.g., BMI1, WEE1, and MCL-1) at the lowest dose level (7.5 mg). At the same time BAX, a marker of pro-apoptosis, showed an increase following treatment.Conclusion:Treatment with CR1-02 was well tolerated and showed biological activity as evidenced by disease stabilization in R/R AML patients. Reduction of CR1-02 targets was achieved beginning at the lowest dose given (7.5 mg/administration), and clinical efficacy signals starting at 11.25 mg/administration. Future investigation is warranted as a promising microRNA-based cancer therapeutics either alone or in combination with other therapeutic agents.Citation Format:Bjørn T. Gjertsen, Andrea Lenartova, Irini Ktoridou-Valen, Cara E. Wogsland, Adam S. Dowrick, Mark Wood, Thomas Dahl, Andrew Fesler, Jingfang Ju. A phase I, open-label, multi-center dose-finding and expansion study to investigate the safety, tolerability, and preliminary efficacy of CR1-02 (5-FU-miR-15a) in patients with acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT059.

01 Mar 2024·Molecular Therapy: Oncology

Development of gemcitabine-modified miRNA mimics as cancer therapeutics for pancreatic ductal adenocarcinoma

Article

Author: Intriago, Erick ; Pal, Amartya ; Ojha, Anushka ; Yuen, John G ; Hwang, Ga-Ram ; Ju, Jingfang ; Fesler, Andrew

Despite the recent advancement in diagnosis and therapy, pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is still the most lethal cancer with a low five-year survival rate. There is an urgent need to develop new therapies to address this issue. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, miR-15a and miR-194, with the chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics, Gem-miR-15a and Gem-miR-194, respectively. In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell-cycle arrest and apoptosis, and these mimics are potent inhibitors with IC₅₀ values up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a and Gem-miR-194 retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a, and FOXA1 for Gem-miR-194. We also found that our Gem-modified miRNA mimics exhibit an enhanced efficacy compared to Gem in patient-derived PDAC organoids. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC.

01 Jan 2024·Genes & Diseases

Development of novel 5-FU modified siRNA against BCL-2 with enhanced efficacy and vehicle-free cellular uptake

Article

Author: Ju, Jingfang ; Hwang, Ga-Ram ; Fesler, Andrew

100 Deals associated with Curamir Therapeutics, Inc.

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100 Translational Medicine associated with Curamir Therapeutics, Inc.

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Pipeline Snapshot as of 20 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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