The LNA-i-miR-221 Phase I trial has been designed as a monocentric open label dose escalation study which received written approval by the Competent Authority and independent Ethics Committee (IEC). LNA-i-miR-221 will be investigated for safety and tolerability in patients, men and women age ≥18 yrs, affected by Refractory-MM and advanced solid tumors.

Start Date14 Jan 2019

Sponsor / Collaborator

Azienda Ospedaliera Universitaria Mater Domini

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100 Clinical Results associated with LNA-i-miR-221

100 Translational Medicine associated with LNA-i-miR-221

100 Patents (Medical) associated with LNA-i-miR-221

Literatures (Medical) associated with LNA-i-miR-221

01 Jun 2024·Molecular Therapy - Nucleic Acids

LNA-i-miR-221 activity in colorectal cancer: A reverse translational investigation

Article

Author: Grillone, Katia ; Tagliaferri, Pierosandro ; Tassone, Pierfrancesco ; Caridà, Giulio ; Staropoli, Nicoletta ; Ciliberto, Domenico ; Fiorillo, Lucia ; Di Martino, Maria Teresa ; Ali, Asad ; Ascrizzi, Serena

Colorectal cancer (CRC) is one of the most common malignancies and a relevant cause of cancer-related deaths worldwide. Dysregulation of microRNA (miRNA) expression has been associated with the development and progression of various cancers, including CRC. Among them, miR-221 emerged as an oncogenic driver, whose high expression is associated with poor patient prognosis. The present study was conceived to investigate the anti-CRC activity of miR-221 silencing based on early clinical data achieved from a first-in-human study by our group. Going back from bedside to bench, we demonstrated that LNA-i-miR-221 reduces cell viability, induces apoptosis in vitro, and impairs tumor growth in preclinical in vivo models of CRC. Importantly, we disclosed that miR-221 directly targets TP53BP2, which, together with TP53INP1, is known as a positive regulator of the TP53 apoptotic pathway. We found that (1) both these genes are overexpressed following miR-221 inhibition, (2) the strong anti-tumor activity of LNA-i-miR-221 was selectively observed on TP53 wild-type cells, and (3) this activity was reduced in the presence of the TP53-inhibitor Pifitrin-α. Our data pave the way to further investigations on TP53 functionality as a marker predictive of response to miR-221 silencing, which might be relevant for clinical applications.

26 Jun 2023·Journal of hematology & oncology

Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study.

Article

Author: Manti, Francesco ; Salvino, Angela ; Ciliberto, Domenico ; Tassone, Pierfrancesco ; Arbitrio, Mariamena ; De Fina, Maria Rosanna ; Caracciolo, Daniele ; Staropoli, Nicoletta ; Zito, Maria Cristina ; Riillo, Caterina ; Di Martino, Maria Teresa ; Brescia, Amelia ; Di Paola, Eugenio Donato ; Scionti, Francesca ; Lopreiato, Mariangela ; Di Francesco, Adele Emanuela ; Tagliaferri, Pierosandro ; Gualtieri, Simona ; Thunarf, Fredrik ; Bertucci, Bernardo ; Fiorillo, Lucia ; Barbieri, Vito ; Cordua, Alessia ; Cuomo, Onofrio

BACKGROUNDWe developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation.METHODSIn this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0-2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33).RESULTSSeventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3-4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose.CONCLUSIONSThe excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).

01 Sep 2020·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Development and validation of bioanalytical methods for LNA-i-miR-221 quantification in human plasma and urine by LC-MS/MS

Q3 · MEDICINE

Article

Author: Morbioli, Lisa ; Solazzo, Lara ; Turtoro, Antonio ; Franzoni, Samantha ; Greco, Alessandro ; Di Martino, Maria Teresa ; Arbitrio, Mariamena ; Tassone, Pierfrancesco ; Tagliaferri, Pierosandro ; Breda, Massimo

LNA-i-miR-221, a 13-mer oligonucleotide, has proved favorable efficacy and safety profiles in the preclinical studies, leading to being approved for use in clinical trials by regulatory authorities. The objective of this study was to develop and validate LC-MS/MS methods to quantify LNA-i-miR-221 in human plasma and urine. Chromatographic separation was performed with a gradient system on HALO C18 column using hexafluoro-2-propanol/triethylamine buffer and methanol as mobile phase. LNA-i-miR-221 was detected on tandem mass spectrometer with electrospray ionization source in negative ion mode. The methods showed good linearity within the calibration range of 50-25000 ng/mL and 50-50000 ng/mL for human plasma and urine, respectively. The methods proved to be accurate, precise and selective in both human matrices. These validated methods are reliable and are currently in use to support a first-in-human clinical trial of LNA-i-miR-221 in patients affected by refractory multiple myeloma and advanced solid tumors.

100 Deals associated with LNA-i-miR-221

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	IT	Azienda Ospedaliera Universitaria Mater Domini	14 Jan 2019
Hepatocellular Carcinoma	Phase 1	IT	Azienda Ospedaliera Universitaria Mater Domini	14 Jan 2019
Multiple Myeloma	Phase 1	IT	Azienda Ospedaliera Universitaria Mater Domini	14 Jan 2019

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