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Characteristics and Attributes of INTASYL™
INTASYL is based on proprietary chemistry that maximizes the activity and adaptability of the compound.
Other siRNA technologies require cell targeting chemical conjugates which limit delivery to specific cell types, but INTASYL is unique because it can be delivered to any cell type or tissue without the need to modify the chemistry. Its simplified composition enables naked compound delivery in buffered saline. There is no need for formulations or delivery systems (for example, nanoparticles or electroporation). This provides efficient, spontaneous, cellular uptake with potent, long-lasting intracellular activity.
Preclinical trials have shown the platform has a favorable toxicity and safety profile. It is well tolerated, regardless of the selected compound.
INTASYL is functional for Intratumoral and Adoptive Cell Therapy (ACT) use. It is efficient for dosing multiple compounds to silence multiple gene targets with essentially no loss of potency. This is in contrast to gene editing, where each new gene edit results in diminishing returns to gene silencing.
Synergies with Antibodies
The INTASYL platform is effective on both extracellular and intracellular targets. Antibodies are limited to extracellular targets. INTASYL, when used in combination with antibodies, resulted in enhanced potency in vivo. The combination of INTASYL with antibodies also increases the number of addressable drug targets. Unlike other antibody combination approaches, the INTASYL platform can target multiple protein drug targets in a specific therapeutic dose, enhancing potency while maintaining a favorable tolerability and safety profile.
Synergies with Cell Therapies
INTASYL precisely targets specific proteins that reduce the body’s ability to fight cancer, without the need for specialized formulations or drug delivery systems. INTASYL has demonstrated preclinical efficacy in Adoptive Cell Therapy (ACT) applications. INTASYL was shown to enhance the activity of ACT therapies, including tumor infiltrating lymphocytes (TILs), chimeric antigen receptor T cells (CAR T), Natural Killer cells (NK) and dendritic cells (DC). INTASYL is easily incorporated into current ACT manufacturing processes.
PH-762 is an INTASYL compound that reduces the expression of cell death Protein 1 (PD-1), a protein that inhibits T cells’ ability to kill cancer cells.
Decreasing the expression of PD-1 increases the capacity of T cells to kill cancer cells. A Phase 1b Dose-escalation study for the treatment of cutaneous squamous cell carcinoma, and metastatic melanoma and Merkel cell is expected to commence in the second half of 2023. In addition, a Phase 1 Adoptive Cell Therapy trial of PH-762 & AgonOx’s Double Positive TILS for the treatment of metastatic melanoma and head and neck cancer is expected to commence in the second half of the year.
PH762 (Presented at AACR, May, 2023)
- Intratumoral mPH-762, a self-delivering RNAi therapeutic (INTASYL™) targeting mouse PD-1, generates systemic tumor-specific memory CD8 T cells, providing a mechanism for abscopal efficacy toward untreated tumors in a murine hepatocarcinoma model
- INTASYL self-delivering RNAi therapeutic dual targeting PD-1 and CTLA-4 provides synergistic antitumor efficacy in the treatment of murine colon cancer in vivo
PH762 (Presented at SITC, November, 2022)
- A Phase 1b study to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of neoadjuvant use of PH-762 administered intratumorally in subjects with advanced melanoma
PH-894 is an INTASYL compound that silences BRD4, a protein that controls gene expression in both T cells and tumor cells, thereby effecting the immune system as well as the tumor. What sets this compound apart is its dual mechanism: INTASYL PH-894 suppression of BRD4 in T cells results in T cell activation; additionally, suppression of BRD4 in tumor cells results in tumors becoming more sensitive to T-cell killing.
PH894 (Presented at SITC, November, 2022)
- PH-894, an INTASYL™ self-delivering siRNA targeting BRD4, has dual functions to sensitize tumor cell killing and activate CD8 T cells
PH-109 is an INTASYL compound that suppresses the Connective Tissue Growth Factor (CTGF) protein, a protein associated with poor prognosis in breast cancer. In a pre-clinical study, mice were treated with either the drug doxorubicin, a chemotherapeutic which has a high toxicity profile, or with PH-109. In this study, PH-109 reduced tumor growth and reduced metastatic lung lesions, with no evidence of toxicity.
PH109 (Presented at SITC, November, 2022)
- Intratumoral PH-109 INTASYL™ self-delivering RNAi targeting connective tissue growth factor (CTGF) provides efficacy in vivo in a mouse model of metastatic breast cancer
CTLA-4: CTLA-4 is a protein that inhibits the ability of T cells to kill tumor cells. The CTLA-4 targeting INTASYL compound demonstrated dose-associated anti-tumor efficacy in two tumor models in vivo. Local delivery may avoid/minimize the severe systemic adverse events associated with current CTLA4 therapeutics.
CTLA4 (Presented at SITC, November, 2022)
- Local immunotherapy with INTASYL™ self-delivering RNAi targeting CTLA-4 provides robust tumor control in vivo
PH-804 is an INTASYL compound that targets TIGIT, a protein that inhibits the activity of Natural Killer (NK) cells. This study demonstrated that NK cells, when treated with PH-804, increased activation and enhanced the ability of NK cells to kill cancer cells.
PH804 (Presented at SITC, November, 2022)
- PH-804, an INTASYL™ self-delivering RNAi compound that targets TIGIT enhances NK cell cytotoxicity to tumor cells
Manufacturing of a Clinical Scale TIL product, with PH-762: This study demonstrated that the Double Positive TIL (DP TIL, AGX148) product can be successfully manufactured at a clinical scale and that DP TILs treated with PH-762 demonstrated durable silencing of PD-1 in vivo for up to 12 weeks and enhanced the efficacy over DP TIL alone. (TIL=Tumor Infiltrating Lymphyocytes).