TP-2846 / Innoviva - LARVOL DELTA

In vivo activities of TP-2846: a novel tetracycline antileukemia agent (AACR 2019) - "TP-2846 demonstrated potent in vivo efficacy in MV4-11 with a Tumor Growth Inhibition (TGI) value of 111.4% (p = 0.001) when dosed IP at 12.5 mg/kg, QD, 4 days on/6 days off, for two cycles, while cytarabine and tigecycline had a TGI value of 23.5% and -49.2%, respectively, at their reported optimal dosing regimens. Subsequent PK/PD modeling using the resulting data sets suggested that AUC is the primary efficacy driver for TP-2846 in the xenograft model.In summary, TP-2846 displayed favorable PK profiles across multiple species and demonstrated potent, dose-responding, AUC-driven efficacy in several mouse leukemia xenograft models. These data sets, combined with other desirable in vitro, in vivo, and chemical-physical properties, support the continued pre-clinical development of TP-2846 as a new antileukemia agent."

Preclinical

In vitro characterization of TP-2846: a novel tetracycline antileukemia agent (AACR 2019) - "TP-2846 had minimal IC50 shift (Resistance Factor (RF) = 1.53) against K-562/ADR, a leukemia cell line overexpressing P-glycoprotein (Pgp), while daunorubicin displayed an RF value of 3.67 in the same assay. TP-2846 was also studied ex vivo using bone marrow samples from 15 AML patients, including those resistant to AraC, and displayed potent activity in all samples (EC50 = 150-250 nM), while anthracyclines had similar activity (EC50 = 100-600 nM) and AraC was 10x less potent (EC50 = 2.3 µM) in the same ex vivo assay.In summary, TP-2846 exhibits both anticancer MOAs described in the literature for tetracyclines, retains antiproliferation activity in resistant leukemia cell lines, and demonstrates promising ex vivo activity in bone marrow samples from AML patients. This data indicates that further investigations in vitro and in vivo are warranted (see accompanying abstract “In vivo activities of TP-2846: a novel tetracycline antileukemia agent”)."

Preclinical

Discovery and structure-activity relationship studies of TP-2846: a novel tetracycline antileukemia agent (AACR 2019) - "TP-2846 demonstrated the highest overall antiproliferation potency against most cell lines tested and is 10-50 folds more potent than tigecycline.Using MV4-11 as the primary screening cell line, we subsequently evaluated and studied the structure-activity relationships of more than 170 analogs of TP-2846 with systematic variations at the C4, C7, and C8 positions of the tetracycline core. Although a number of new analogs displayed comparable antiproliferation activity in MV4-11, TP-2846 remains the most potent analog overall in vitro and was selected to be further profiled in vitro and in vivo (see accompanying abstracts “In vitro characterization of TP-2846: a novel tetracycline antileukemia agent” and “In vivo activities of TP-2846: a novel tetracycline antileukemia agent”)."

Tetraphase Pharmaceuticals presents preclinical data on TP-2846, a novel drug candidate for acute myeloid leukemia (Businesswire) - "Tetraphase Pharmaceuticals, Inc...announced data from its preclinical program for TP-2846, the Company’s new pipeline candidate for acute myeloid leukemia (AML) discovered using Tetraphase’s proprietary total synthesis platform....'We are very encouraged by these early data, which suggest that TP-2846 holds the potential to benefit AML patients regardless of their mutation status.'"

Preclinical

Newly added product (Businesswire) - Preclinical, Acute Myelogenous Leukemia

Pipeline update