Codiak BioSciences, a clinical-stage biopharmaceutical company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, today reported new preclinical evidence from Codiak’s exoASO-STAT6 program and clinical results from the healthy volunteer portion of the ongoing Phase 1 trial of Codiak’s exoIL-12 program at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021. These data illustrate the potential of engineered exosomes to target previously undruggable but well-validated pathways in cancer immunotherapy and generate potent single-agent activity.
“We now have a growing body of preclinical and clinical evidence across our pipeline programs demonstrating that engineering exosomes to deliver potent drug molecules enhances the therapeutic index of pathways known to drive the immune response to fighting tumors,” said Douglas E. Williams, Ph.D., President and Chief Executive Officer of Codiak. “In particular, data from multiple in vitro and in vivo studies of engineered exosomes incorporating an antisense oligonucleotide demonstrate potent single-agent and highly selective genetic reprogramming of tumor associated macrophages, which is unique among macrophage targeting strategies. We look forward to advancing our exoASO-STAT6 candidate into clinical trials following our Investigational New Drug application (IND) filing anticipated later this year.”
Both exoASO-STAT6 and exoIL-12 were developed via Codiak’s proprietary engEx™ Platform, which enables the company to engineer exosomes – naturally occurring, extracellular vesicles – with distinct properties, load them with various therapeutic molecules and alter tropism so they reach specific cellular targets. exoIL-12 is currently being evaluated in a Phase 1 clinical trial in patients with cutaneous T cell lymphoma (CTCL) and is one of two Codiak programs in human clinical testing.
exoASO-STAT6 Results in Potent Single-Agent Complete Anti-Tumor Response in Multiple Preclinical Models
M2 phenotype macrophages promote tumor growth by creating a highly immunosuppressive environment in the tumor. exoASO-STAT6 is a novel therapeutic candidate designed to deliver antisense oligonucleotides (ASOs) to selectively target STAT6, a key immunosuppressive transcription factor in tumor associated macrophages (TAMs). Codiak plans to focus clinical development of exoASO-STAT6 initially in myeloid rich cancers such as colorectal cancer, hepatocellular carcinoma (HCC) and others.
Results from multiple in vitro and in vivo studies demonstrate that exoASO-STAT6 effectively reprograms macrophages to a pro-inflammatory M1 phenotype, resulting in potent single-agent anti-tumor activity. exoASO-STAT6 exhibits a selective tropism for myeloid cells and delivered up to 12-fold more ASO to M2 macrophages in vivo than ASO administration without an exosome (e.g., “free”).
In vivo studies with exoASO-STAT6 in two syngeneic tumor models (CT26 and Hepa 1-6) consistently demonstrated potent single-agent activity. Monotherapy with exoASO-STAT6 resulted in 60% complete tumor remission in CT26 tumors. Notably, free STAT6 ASO showed no anti-tumor activity at the same dose, highlighting the enhancement in ASO therapeutic efficacy conferred by exosomes. Intravenous administration of exoASO-STAT6 in mice bearing Hepa1-6 orthotopic HCC tumors also resulted in profound reduction (62%) of tumor burden. In contrast, anti-CSF1R or anti-PD1 therapy as a comparator did not result in any measurable effects on tumor growth in either model.
In both tumor models, monotherapy activity of exoASO-STAT6 is accompanied by a substantial remodeling of the tumor microenvironment (TME), as evidenced by marked increase in pro-inflammatory markers such as iNOS positive monocyte/macrophages, one of the hallmarks of effective M1 macrophage reprogramming, and reduction in immunosuppressive markers such as CD163. Subsequent genetic and histology analyses confirmed remodeling of the TME to a pro-inflammatory M1-like phenotype induced by exoASO-STAT6 therapy.
exoIL-12 Demonstrates Local Pharmacology, Tolerability and Absence of Systemic IL-12 Exposure in Healthy Volunteers
IL-12 is a potent anti-tumor cytokine; however, translating IL-12 into a drug in the clinic has generally been hindered by significant safety and tolerability concerns. To overcome these limitations, exoIL-12 was designed to facilitate dose control of IL-12 and limit systemic exposure and associated toxicity by localizing IL-12 in the TME to potentially expand the therapeutic index.
Previously reported pharmacokinetic and pharmacodynamic data from the randomized, placebo controlled, double-blind Phase 1 study showed that administration of exoIL-12 in healthy volunteers resulted in a favorable safety and tolerability profile and prolonged pharmacodynamic effect with no local or systemic treatment-related adverse events and no detectable systemic exposure of IL-12. In particular, a subcutaneously administered single ascending dose of exoIL-12 demonstrated no systemic exposure across the dose range (0.3-12.0 μg), which is in direct contrast to previous clinical studies with recombinant IL-12. New pharmacodynamic data presented at AACR 2021 show no systemic IFN-γ production, which may further explain the favorable safety and tolerability of exoIL-12.
Pharmacodynamic data from skin punch biopsies showed detectable levels of exoIL-12 in the skin at the 6.0 μg dose as much as 24 hours post injection, indicating retention at the injection site and prolonged activation of the IL-12 signaling cascade. Based on these findings, the 6.0 μg dose level has been selected for the second portion of the Phase 1 trial currently underway, where the safety and efficacy of exoIL-12 will be evaluated following repeat doses into the lesions of patients with early-stage CTCL.
Source – EIN Presswire