On April 18, 2018 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing Pentarins as a new class of potent and selective cancer medicines, reported that presented data on the efficacy of PEN-866, a novel miniature drug conjugate comprised of a Heat Shock Protein 90 (HSP90) targeting ligand attached through a cleavable linker to SN-38 when combined with Poly ADP ribose polymerase (PARP) inhibitors in preclinical models of human cancer (Press release, Tarveda Therapeutics, 18 18, 2018, View Source [SID1234525520]). SN-38 is a potent topoisomerase 1 inhibitor, and is the active metabolite of irinotecan. The poster titled, "Combination of the miniature drug conjugate PEN-866 with PARP inhibitors as a rational approach to overcoming limitations of PARP inhibitor monotherapy" was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 14-18, 2018 in Chicago.
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The data presented evaluates the use of PEN-866 in combination with PARP inhibitors as an approach to overcoming limitations of PARP inhibitor monotherapy, such as dose limiting toxicities, in preclinical models of human cancer. In efficacy studies carried out in both BRCA mutant and BRCA wildtype tumor xenografts, combinations of PEN-866 and PARP inhibitors resulted in greater efficacy than that of the monotherapy in both tumor types.
"Results presented today show that when combined with PARP inhibitors, PEN-866 could avert the dose limiting toxicities often seen when PARP inhibitors are combined with other anti-cancer therapies," said Richard Wooster, Ph.D., President of Research and Development and Chief Scientific Officer of Tarveda Therapeutics. "The high levels of accumulation and retention of the combination of PEN-866 and a PARP inhibitor in xenograft tumors demonstrate the potential for greater efficacy compared to single agent therapy."
PEN-866’s linker cleavage provides sustained release of SN-38 at a high local tumor concentration leading to DNA damage and apoptosis of tumor cells, which results in broad antitumor activity in a range of preclinical xenograft models. When PEN-866 is administered in combination with PARP inhibitors, the inhibitors reduce DNA repair activity in tumor cells, enabling PEN-866 to maximize its efficacy in damaging cancer cell DNA. A pharmacodynamic assessment of DNA damage performed in tumors responsive to the combination treatment further demonstrated the efficacy of the therapy.
"The mechanistic synergy of PEN-866, carrying the payload SN-38 which is a potent topoisomerase I inhibitor, and PARP inhibitors suggests that this combination therapy could be an attractive approach in the clinical evaluation of PEN-866," said Drew Fromkin, President and Chief Executive Officer of Tarveda Therapeutics. "We look forward to continued studies of PEN-866, including our first-in-human Phase 1 clinical trial of PEN-866 to evaluate safety and efficacy."
About PEN-866
PEN-866 exploits the activation of Heat Shock Protein 90 (HSP90) in tumors to accumulate and release its potent anti-cancer payload, SN-38. PEN-866 is a miniature conjugate that comprises a small molecule, HSP90-targeting ligand linked to SN-38, the active metabolite of irinotecan. The conjugate accumulates and is retained in tumors and, by way of a sustained release of SN-38, causes prolonged DNA damage and tumor regressions in multiple patient-derived and other xenograft tumor models. PEN-866 is currently being studied in first-in-human clinical trials to evaluate safety and efficacy in patients with advanced solid tumors.
About Pentarins
Tarveda is developing Pentarins, potent and selective miniature drug conjugates with high affinity for specific cell surface and intracellular targets. Pentarins are engineered to bind to their tumor cell targets and provide sustained release of their potent therapeutic payloads deep into solid tumor tissue. Comprised of a targeting ligand conjugated to a potent cancer cell killing agent through a tuned chemical linker, Pentarins are designed to overcome the deficits of both larger antibody drug conjugates and small molecules that limit their therapeutic effectiveness against solid tumors. Together, the components of Tarveda’s Pentarins have distinct, yet synergistic, anticancer attributes: the small size of Pentarins allows for rapid and deep penetration into the tumor tissue, the ligand’s targeting ability allows for specific binding and retention in tumor cells, and the chemical linker is tuned to optimize the release of the potent, cell killing payload inside the cancer cells for efficacy.