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Marina Biotech, Inc. Message Board

  • moose_catcher moose_catcher Nov 16, 2012 5:46 AM Flag

    MRNA, PRONAI Abstract w/Results P1

    This is HUGE for MRNA:

    A Study of PNT2258 (DNA-targeted Blocker of BCL2 Expression) in Patients with Advanced Solid Tumors
    D.W. Rasco1, A. Patnaik1, A. Amaya1, S. Gaylor2, T. Moore3, E. Izbicka4, R. Streeper4, W. Rodrigueza4, R. Messmann4, A. Tolcher1
    1South Texas Accelerated Research Therapeutics, Phase 1 Unit, San Antonio TX, USA ; 2Veeda Oncology, Clinical Affairs, Columbus OH, USA ; 3Mid-Ohio Oncology Hematology, Clinical Affairs, Columbus OH, USA ; 4ProNAi Therapeutics Inc., Clinical Affairs, Plymouth MI, USA

    Background: The BCL2 protein plays a key and central role in the regulation of apoptosis and derangement of this control mechanism is a defining characteristic of malignant cells. ProNAi Therapeutics, Inc. has developed a unique approach to selectively block transcription of BCL2 and other oncogenes called DNA interference (DNAi) in which a single stranded DNA oligonucleotide is delivered to cancer cells via a protective liposomal transport system. After cellular entry, the DNAi drug is released to bind to genomic DNA, inhibiting BCL2 transcription and causing pro-apoptotic events that lead to cancer cell death. This phase I study, conducted at South Texas Accelerated Research Therapeutics (START), is the first-in-human assessment of PNT2258 as a DNA-targeted blocker of BCL2 expression. The primary and secondary endpoints of the study included determination of the drug safety profile, identification of a phase 2 trial dose, the analysis of BCL2 biomarker data and the evaluation of PK/PD relationships.

    Material and Methods: Patients with treatment-refractory solid tumors, PS 0–2 and adequate organ function were treated with PNT2258 on days 1–5 of a 21-day cycle. PBMC samples and plasma were taken for analysis of surrogate biomarkers and to identify changes in total BCL2 and phosphorylated BCL2 protein levels as well as active PARP/BCL2 and active caspase-3/BCL2 ratios; the latter as indicators of increased apoptosis. Additional markers of BCL2 inhibition and cancer markers were also included in the analysis of plasma.

    Results: Twenty-two patients received PNT2258 at doses ranging from 1 to 150mg/m2, constituting over 60 cycles and 300 doses. PNT2258 was well tolerated at all dose levels with G1–2 fatigue as the most common adverse event (10.3%; 8 of 79 events). No allergic sequelae occurred. Two patients at 150mg/m2 manifested 2 reversible DLTs: G3 increase in LFTs and G4 thrombocytopenia, defining the MTD for this schedule. Preliminary PK analysis shows biphasic elimination from circulation with Cmax and AUC increasing linearly with dose. PBMC analysis confirmed dose-dependent, statistically significant decrease in levels of BCL2 and phosphorylated-BCL2, increased PARP cleavage, caspase-3 activation, lymphocyte reductions, and increases in plasma leptin. These and additional results confirm that PNT2258 effectively targets genomic bcl2 to drive apoptosis.

    Conclusions: PNT2258 is safe and well tolerated and phase 2 clinical trials will use PNT2258 at a dose of 120mg/m2 IV on days 1–5 of a 21-day schedule. BCL2 protein levels decreased and apoptotic markers increased with increasing dose and PK analysis indicates significantly higher drug exposure levels in humans than those required to achieve anti-tumor efficacy in animal tumor models. Additional clinical studies are now being implemented to confirm proof-of-efficacy in BCL2 driven tumor populations including patients with diffuse large B-cell lymphoma and chronic lymphocytic leukemia.

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