Our Pipeline of RNAi Therapies
Phio is developing a pipeline of RNA inference (RNAi) therapies that have the ability to attack cancers in multiple ways.
INTASYL™-based therapeutics can:
1. Strengthen immune cells, for example those administered as part of adoptive cell therapy and
2. Directly modify cells in the tumor microenvironment to weaken a tumor’s defense.
These 2 strategies allow for multiple therapeutic applications of INTASYL™ products.
Our lead product, PH-762, activates immune cells to better recognize and kill cancer cells. It does so by reducing the expression of PD-1, a clinically validated target for immunotherapy. PD-1 is expressed by T-cells and helps keep them from killing other cells, including cancer cells. Reducing PD-1 expression can reduce the ability of cancer cells to avoid T-cell detection. Like any other INTASYL™ self-delivering RNAi therapeutic, it can be used either via local administration to a tumor (to modify the tumor microenvironment); or to improve immune cells for ACT.
PH-894 targets bromodomain-containing protein 4 (BRD4), which is an intracellular regulator of gene expression that impacts cell differentiation, and hence, cell function. BRD4 is also known as an oncogenic driver in multiple cancer types. This makes BRD4 an attractive target pursued by pharmaceutical companies, but it is a protein that has been shown to be hard to target with current drug modalities. Since it is an intracellular protein, antibody therapies cannot be used, and the small molecule inhibitors tested to date typically lack the required specificity. Considering INTASYL™ can target extracellular as well as intracellular proteins with a high level of specificity, PH-894 has significant potential.
PH-804 silences the suppressive immune receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), which is a checkpoint protein present on immune cells, such as T-cells and NK cells. TIGIT is one of the most recent immune checkpoints to be investigated as an immunotherapeutic target. Similar to PD-1, cancer cells can suppress the activity of these immune cells by activating TIGIT. This triggers an “off switch”, resulting in tumor immune evasion, which can be prevented by blocking or silencing TIGIT.
To better understand how our technology is driving several pipeline opportunities in both ACT and direct-to-tumor therapy, see toggle below.
Adoptive Cell Therapy Products
INTASYL™ Pipeline for Adoptive Cell Therapy Applications
- PH-762 reduces the expression of the immunosuppressive protein PD-1 in T-cells used for ACT, enabling them to overcome tumor resistance mechanisms and thus improving their ability to destroy the tumor cells.
- Preclinical studies have shown how PH-762 can activate human T-cells grown for ACT and how it can increase their tumor cell-killing ability. The tumor-killing potency of these PH-762 T-cells against the tumor cells of the same patient was increased by about 2 fold as compared to untreated T-cells. As a result, the use of PH-762-treated ACT is expected to enhance therapeutic responses in cancer.
- Data, completed in partnership with the Karolinska Institutet in Sweden, demonstrated that the application of PH-894 can silence BRD4 in human T-cells while being grown for ACT.
- It was also shown that T-cells treated with PH-894 have increased antitumor activity.
- PH-804 provides powerful dose-dependent silencing of TIGIT that can be seen in both T-cells and NK cells.
- In addition, PH-804 has demonstrated induced silencing of TIGIT in NK cells and T-cells, which can overcome their “off switch” with the cells becoming weaponized to kill cancer cells.
INTASYL™ Pipeline for Direct-to-Tumor Applications
- Through local administration of PH-762, we can reprogram the tumor microenvironment (TME) and achieve local activation of immune cells.
- The potential of such direct therapeutic use of PH-762 has been demonstrated in animal studies. Administration of PH-762 through intratumoral injection resulted in potent antitumoral effects, whereby the treated animals showed a complete and statistically significant inhibition of tumor growth. In contrast, placebo-treated animals displayed exponential tumor growth.
- Direct injection of INTASYL™ therapeutics can successfully penetrate solid tumors and impact the TME by activating the immune response in animal models of solid tumors, resulting in reduced tumor growth. Based on our positive preclinical data, we are preparing for a clinical study with PH-762 using intratumoral administration for patients with advanced melanoma.
- Data published by Phio showed the use of PH-894 in a validated mouse model of hepatocellular carcinoma. In this study, local administration of PH-894 through intratumoral injection resulted in potent and statistically significant antitumoral effects.
- PH-894 shows the power of INTASYL™ to modulate expression of intracellular and/or commonly considered ‘undruggable’ targets, a limitation for small-molecule and antibody therapies.