On April 27, 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 that new pharmacokinetic and target engagement data from its Phase 1 study of PEN-866 in patients with solid tumor malignancies at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Tarveda Therapeutics, APR 27, 2020, View Source [SID1234556654]). PEN-866 is the initial clinical program from Tarveda’s HSP90 binding miniature drug conjugate platform, and is designed to bind to activated Heat Shock Protein 90 (HSP90) to accumulate and release its potent topoisomerase 1 inhibitor (SN-38) payload in solid tumors. The poster titled, "Characterization of PEN-866, a Heat Shock Protein 90 (HSP90) binding conjugate of SN-38, in patient plasma and tumors from the first in human study", showcased confirmatory pharmacokinetics of PEN-866 in patient plasma and highlighted data from two patient biopsies, which confirmed higher concentrated levels of the PEN-866 conjugate and SN-38 payload in tumor relative to plasma.

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"The plasma pharmacokinetic data from the dose escalation portion of our Phase 1/2a clinical trial demonstrated that PEN-866 exhibited favorable plasma pharmacokinetics as predicted from our preclinical data, with PEN-866 remaining intact while in circulation. Unconjugated SN-38 remained very low at approximately 2% of the PEN-866 exposure in circulation," said Mark Bilodeau, Ph.D., Chief Scientific Officer of Tarveda. "We are also very encouraged by the tumor biopsy data, which showed tumor uptake and retention of PEN-866 as well as the subsequent release of SN-38, which was significantly increased in comparison to the presence of PEN-866 and released SN-38 in plasma at days 1 and 7/8 after dosing. These data are consistent with PEN-866 preclinical data showing materially increased uptake and retention of PEN-866 in the tumor versus untargeted forms of SN-38, such as irinotecan."

Dr. Bilodeau continued, "the preferential tumor targeting and release of SN-38 seen in the tumors with PEN-866 serves as a firm foundation for the broader potential of the platform to produce new HSP90 binding miniature drug conjugates with promising anti-cancer payloads."

"The clinical and preclinical results seen to date show that PEN-866 accumulates and is retained in tumors where it is then released over multiple days at therapeutic levels. This is in contrast to plasma where the conjugate remains intact and is quickly cleared from the circulation, helping to spare potential damage to normal tissue," said Jeffrey Bloss, M.D., Chief Medical Officer of Tarveda. "These data support the miniature conjugate design of PEN-866 and are a contributor to the beneficial therapeutic index seen with PEN-866 in Phase 1. We are excited to work with PEN-866 in Phase 2a and believe its development should be explored as a single agent and in combination with other exciting therapeutics, such as PARP inhibitors and immuno-oncology drugs that have struggled to successfully combine with cytotoxic therapies."

PEN-866 Phase 1 Study Design & Results

Thirty patients with advanced solid tumor malignancies were enrolled in the Phase 1 dose escalation cohorts and received PEN-866 on days 1, 8, and 15 in 28-day cycles over a dose range of 16-228 mg/m2. The PEN-866 plasma concentration profile showed a concentration decline after end of infusion resulting in an average half-life of approximately 7 hours. PEN-866 plasma concentrations up to 39 µg/mL and area under the concentration curve of 57 h·µg/mL were achieved and determined for the recommended Phase 2a dose. Of the 30 patients, two consented to tumor biopsy collection to determine PEN-866 and SN-38 accumulation. Biopsy results from a pancreatic cancer patient who received a 150 mg/m2 dose of PEN-866 showed that PEN-866 and SN-38 levels in the tumor were significantly higher than observed in plasma 24 hours post dose and that the ratio of SN-38 to PEN-866 was high in tumor and low in plasma. Results from a patient with esophageal cancer who received a 175 mg/m2 dose of PEN-866 on day one and underwent tumor biopsy on day seven showed continued exposure of PEN-866 and SN-38 in the tumor. While in the plasma, PEN-866 was extremely low and SN-38 was unmeasurable (on day 8). These biopsy results support previous preclinical data showing that PEN-866 slowly releases its SN-38 payload in the tumor over multiple days.

Overall the data show that PEN-866 demonstrated favorable plasma pharmacokinetics with low levels of SN-38 observed in plasma. More importantly, both the conjugate and released payload (SN-38) were concentrated and retained in the tumor for up to a week. PEN-866 recently completed the Phase 1 all-comers, dose escalation and safety portion of a Phase 1/2a clinical trial. Additional information on the Phase 1/2a clinical trial for PEN-866 is available at clinicaltrials.gov, through identifier number NCT03221400.