GRN163L, a Potent and Specific Inhibitor of Telomerase: Integrated Pharmacokinetic, Pharmacodynamic, and Safety Data Guides Design of Practical Treatment Regimens for Targeting Inhibitory Levels in Patients.
Authors: Tressler Robert J. , Chin Allison C. , Feldman Eric J. , Rai Kanti R. , Kornbrust Doug , Harley Calvin B. , Behrs Melissa A. Kelly , Elias Laurence 
Published: October 2019

Abstract
GRN163L is a lipidated thiophosphoramidate oligonucleotide that binds with nanomolar affinity to the template region of human telomerase RNA, causing direct enzyme inhibition. Cellular IC50 values range from 0.8 to 6.5 μg/mL among 13 solid and hematologic tumor lines, and GRN163L inhibits tumor growth in multiple human tumor xenograft studies. Due to the high affinity and slow off-rate of binding, telomerase inhibition is long-lasting following exposure to the drug (Oncogene, 2005, 24, 5262). Previously reported studies demonstrated that exposure of human myeloma cell lines INA6 and ARP to 1 μM GRN163L resulted in ≥ 90% inhibition of telomerase activity and was followed by reduced cell growth and survival (Masood et al, ASH 2005). GRN163L uptake and telomerase inhibition have also been demonstrated in primary human CLL cells tested at 2 μM (Lin et al., ASH, 2005). Many polyanionic oligonucleotides can cause reversible inhibition of the intrinsic coagulation pathway and complement activation at high concentrations. The studies reported here were designed to determine safe and well-tolerated dose schedules and dose ranges for GRN163L in primates in order to attain plasma levels effective for telomerase inhibition and anti-tumor effects.
Methods: GRN163L was administered i.v. to cynomolgus monkeys at varying doses and infusion durations. Plasma levels were determined using a validated hybridization-ELISA method.
Results: In multiple studies, the T½α from two compartment modeling was 2.9 to 5.3 hr for doses of 5 to 15 mg/kg. Actual (from separate but representative studies) and modeled peak plasma levels (Cmax) as well as duration of plasma levels above the 1 μM (~4.8 μg/mL) cellular telomerase inhibitory level are shown in the table below.
5 mg/kg dose Observed Cmax From Model Inf Dur Mean ±SD Cmax Level ≥ 1 μg/ml hrs μg/ml hrs Bolus 185±8 153 15 0.5 200±16 144 16 2 128±3 122 16 6 63±9 83 19
At 10 mg/kg over 6 h, Cmax was 90–115 μg/mL, with < 2-fold increases in APTT and no significant complement activation. Repeated doses up to 15 mg/kg were well tolerated at all infusion durations. A Phase I/II clinical trial of GRN163L infusions in CLL patients is in progress and the observed T½α values from initial cohorts are consistent with the model presented here.
Conclusions: Due to the relatively long T½α of GRN163L, telomerase inhibitory concentrations should be attainable with clinically practical infusions of 1 to 6 hr duration without dose-limiting peak plasma concentrations. Given the high target affinity, such infusions repeated intermittently could maintain near continual target inhibition. GRN163L is the first telomerase targeted agent to enter clinical trials. Initial results from these clinical trials support the hypothesis that telomerase inhibitory levels can be achieved at well tolerated doses.