On March 28, 2022 Synthetic Biologics, Inc. (NYSE American: SYN), a diversified clinicalstagecompany developing therapeutics designed to treat diseases in areas of high unmet need, reported the peer-reviewed publication of a Phase 1, multicenter, open-label, dose-escalation studyinvestigating the therapeutic potential of intravenous VCN-01 oncolytic adenovirus with or withoutstandard-of-care (SoC) chemotherapy (gemcitabine/nab-paclitaxel) in patients with advanced solidtumors (Press release, VCN Biosciences, MAR 30, 2022, View Source [SID1234611126]). The data, published in the Journal for ImmunoTherapy of Cancer, suggests that treatment withVCN-01 is feasible and has an acceptable safety profile, with encouraging biological and clinical activity.These findings provide valuable dose-finding context and inform the clinical development strategy forVCN-01.
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"The results in this publication support VCN-01 administration intravenously at doses ≥3.3x1012vp/patient, resulting in viral exposure in the primary tumor and liver metastases, replication within thetumor, and the potential to remodel the tumor matrix to further promote tumor inflammation," saidManel Cascallό, Ph.D., General Director of Synthetic Biologics’ European Subsidiary. "These clinical dataunderscore VCN-01’s differentiated mechanism of action and were used to inform our Phase 2 study inpatients with metastatic pancreatic adenocarcinoma, which is expected to initiate in the second half of2022. More broadly, these results will help guide our rapidly advancing clinical program for VCN-01 andfurther support the development of our novel OV platform."
In the Phase 1, multicenter, open-label, dose-escalation study (NCT02045602), researchers evaluatedthe administration of a single dose of VCN-01 alone, in patients with solid tumors (Part I), or incombination with SoC chemotherapy (gemcitabine/nab-paclitaxel) in patients with locally advanced ormetastatic, unresectable, pancreatic adenocarcinoma (Parts II and III). In Part II, the VCN-01 wasadministered on the same day as the first dose of chemotherapy (Concomitant Regimen) and in Part IIIthe VCN-01 was administered 7-days prior to the first dose of chemotherapy (Sequential Regimen). Theobjective was to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01adenovirus.
Overall, systemic VCN-01 was well tolerated in the patient population. The most common treatmentrelatedadverse events (AEs) were pyrexia, flu-like symptoms and increases in liver transaminases. These AEs were dose-dependent, reversible and consistent with AEs previously described for other adenovirusbasedproducts. In Part II, transient increases in neutropenia and thrombocytopenia were observedwhen VCN-01 in combination with gemcitabine/nab-paclitaxel was administered using the ConcomitantRegimen, and one patient suffered a fatal episode of enterocolitis and thrombocytopenia. The AE profilewas significantly reduced in Part III when VCN-01 and gemcitabine/nab-paclitaxel was administeredusing the Sequential Regimen, and was similar to the observed AE profile when VCN-01 wasadministered alone. There were no dose limiting toxicities observed in patients administered VCN-01using the Sequential Regimen. The investigators determined the RP2D was 1×1013 viral particles(vp)/patient in Part I and Part III, and 3.3×1012 vp/patient in Part II.
The Phase 1 study provided encouraging clinical results and further confirmed the proposed VCN-01mechanism of action. In patients with pancreatic adenocarcinoma, overall response rates were 50%(Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies(primary pancreatic tumor and liver metastases) on day eight. A second peak of virus concentrations inplasma and increased serum hyaluronidase levels suggest replication after IV injection in all patients.Higher peaks of hyaluronidase serum levels were associated with maximum tumor shrinkage andincreased levels of immune biomarkers (IFNγ, sLAG3, IL-6, IL-10) were found in sera after VCN-01administration. Several markers of tumor inflammation (including CD8 infiltration and indoleamine 2, 3-dioxygenase [IDO] upregulation) were described in tumor biopsies indicating that VCN-01 promotes achange in the tumor immune environment.
Synthetic Biologics anticipates the initiation of multiple international studies, including a Phase 2 clinicaltrial of intravenous VCN-01 in combination with SoC chemotherapy using the Sequential Regimen as afirst-line therapy in newly diagnosed metastatic pancreatic adenocarcinoma patients in the fourthquarter of 2022, as well as a Phase 2/3 pivotal trial of intravitreal VCN-01 as either an adjunct tochemotherapy or a potential rescue therapy in pediatric patients with advanced retinoblastoma in early2023.