On August 4, 2020 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company developing a new class of potent and selective precision oncology medicines, which it refers to as Pentarin miniature drug conjugates, reported the publication of its preclinical study evaluating its HSP90 binding miniature drug conjugate with a pan-PI3K payload, T-2143, in solid tumors (Press release, Tarveda Therapeutics, AUG 4, 2020, View Source [SID1234562839]). The publication, titled "Novel Miniaturized Drug Conjugate Leverages HSP90 Driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors," was published in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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"The PI3K pathway is one of the most frequently dysregulated signaling cascades in cancer and is implicated in a wide range of tumor types. Successful drug development of PI3K inhibitors has been very limited however, due to toxicity observed across numerous programs," said Mark Bilodeau, Ph.D., Chief Scientific Officer of Tarveda. "We have been able to leverage our HSP90 binding miniature drug conjugate platform to develop T-2143, designed to target a pan-PI3K inhibitor selectively to the activated HSP90 in solid tumors, and to mask the activity of the pan-PI3K inhibitor until it is released preferentially in the tumor, which further enhances the systemic tolerability of the payload. The results of the study published today confirm that T-2143 had superior efficacy to a non-targeted pan-PI3K inhibitor alone in a pre-clinical xenograft model, and that the tumor targeting and payload masking successfully reduced hyperglycemia, one of the most common dose-limiting toxicities in this class."

"The T-2143 conjugate design sets the stage for a potentially differentiated pan-PI3K inhibitor, with an improved efficacy and safety profile over existing pan-PI3K inhibitors alone," said Kapil Dhingra, M.D., a leading oncology therapeutics expert and member of the Tarveda Scientific Advisory Board. "The encouraging results of this preclinical study show that T-2143 was able to significantly inhibit tumor growth without the hyperglycemia commonly seen as a dose-limiting toxicity of inhibitors of PI3Ka including the pan-PI3K inhibitor class. If proven in human clinical trials, this approach has the potential to deliver improved efficacy of this important class of inhibitors, with applicability across a wide range of tumor types. As the second drug candidate from this novel platform, this data further supports the notion that HSP90 binding miniature conjugates can allow tumor specific accumulation and retention of a variety of payloads that may address unmet medical needs across a broad spectrum of tumor types, without the usual limitations encountered by antibody-drug conjugates."

The results of the study detail how our HSP90 targeted pan-PI3K inhibitor drug conjugate, T-2143, demonstrates rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy in tumor xenograft models than the marketed pan-PI3K inhibitor, copanlisib, on its own. Data from the study show that by leveraging the preferential accumulation of HSP90 targeted conjugates and its payload in tumors, T-2143 can selectively target a pan-PI3K inhibitor, leading to efficacy in multiple xenograft tumor models. The selective targeting of T-2143 and the masking of the inhibitor active site enabled mitigation of hyperglycemia, a dose limiting side effect seen in pan-PI3K inhibitors, while driving higher tumor exposure and enhanced efficacy. The targeted drug conjugate strategy employed in the design of T-2143 is based on Tarveda’s HSP90 binding drug conjugate platform and shows the potential to provide new treatment options to patients with solid tumor malignancies through specific tumor targeting of anticancer payloads and the reduction of toxicity through selective tumor targeting as well as payload masking.