Pipeline
of Selective Translation Regulator Inhibitors
Program
(Target)
Discovery
Preclinical
Phase 1
Phase 2
tomivosertib
(MNK1/2)
Combination
Indication | CPI-A: Combination Add-on to Approved Checkpoint Inhibitors
Indication | Advanced Breast Cancer Combination with Paclitaxel*
zotatifin
(elF4A)
Indication | Solid Tumors
Indication | Solid Tumors
*Led by McGill University; fully funded by a grant from Stand Up to Cancer Canada
Tomivosertib inhibits MNK1/2,
a central regulator of immune attenuation
1
2
3
4
5
6
7
1
Release of tumor cell antigens
(tumor cell death)
eFT508
Survival Factors
2
Tumor antigen presentation
(dendritic cells/APCs)
eFT508
Antigen Presentation
3
Priming and activation
(APCs & T cells)
eFT508
Activate T cells
APC Trafficking
Anti-CTLA4
4
Trafficking of T cells to tumors
(CTLs)
5
Infiltration of T cells into tumors
(CTLs, endothelial cells)
6
Recognition of tumor cells by T cells
(CTLs, tumor cells)
7
Killing of tumor cells
(Immune & tumor cells)
eFT508
Checkpoint Proteins
Anti-PD-1, PD-L1
Release of
tumor cell antigens
tumor cell antigens
Release of tumor cell antigens
(tumor cell death)
eFT508
Survival Factors
Tumor
antigen presentation
antigen presentation
Priming
and activation
and activation
Trafficking of
T cells to tumors
T cells to tumors
Infiltration of
T cells into tumors
T cells into tumors
Recognition of
tumor cells by T cells
tumor cells by T cells
Killing of
tumor cells
tumor cells
Tomivosertib (also known as eFT508) is a novel, potent and highly selective oral small molecule inhibitor of mitogen-activated protein kinase interacting kinases 1 and 2, or collectively, MNK1/2. MNK1/2 play a crucial role in the development of many tumors, including by controlling in a coordinated manner the expression of multiple factors that attenuate an immune response.
The interaction between a patient’s tumor and immune system has been described as a cyclical process referred to as the cancer immunity cycle. Our studies have shown that tomivosertib acts on multiple points in the cancer immunity cycle simultaneously, underscoring its therapeutic potential in combination with existing checkpoint inhibitor treatments. Our preclinical and clinical studies suggest combining tomivosertib with a checkpoint inhibitor can overcome mechanisms of resistance to checkpoint inhibitors, resulting in enhanced sensitivity to checkpoint inhibitors and a higher response rate. In addition, our preclinical data demonstrate that tomivosertib as a single agent promotes antitumor immunity that persists after stopping drug treatment.
We are completing a 39 patient Phase 2 trial with tomivosertib in combination with checkpoint inhibitors. Tomivosertib is added as a combination therapy to patients already receiving checkpoint inhibitors in FDA-approved indications and experiencing insufficient response to their checkpoint therapy alone (CPI-A). Tomivosertib will also be studied in combination with paclitaxel to treat patients with metastatic breast cancer in a 40 patient Phase 2a trial in Canada fully funded by Stand Up to Cancer (SU2C) Canada.
Zotatifin (eFT226)
Zotatifin (also known as eFT226) is a highly potent and selective small molecule inhibitor of eIF4A (eukaryotic initiation factor 4A), a strong anti-proliferative target located downstream from both the RAS and PI3K signaling pathways. We have demonstrated that eIF4A inhibition selectively regulates the translation of a distinct set of target mRNA that include a number of important oncogenes and survival factors, including – KRAS (independent of mutation subtype), certain receptor tyrosine kinases (RTKs) such as EGFR, HER2 and FGFR 1/2, and cell cycle proteins including Cyclin D1 and CDK4/6 (common resistance mechanisms for targeting therapies). Oncogenes are genes that—when altered by mutation, activation or gene amplification—can contribute to the growth of tumors and are known to drive proliferation and avoidance of antiproliferative signals in tumors. Preclinical studies have shown that zotatifin is active in tumor models of colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B cell lymphomas. We dosed our first patient in a Phase 1 clinical trial to assess zotatifin in solid tumors in November 2019.
eIF4E
Eukaryotic initiation factor 4E (eIF4E) is an oncogenic target involved in the initiation of translation of key disease-driving proteins. eFFECTOR Therapeutics and Pfizer, Inc. announced on January 9, 2020 an exclusive worldwide license and collaboration agreement to develop small molecule eIF4E inhibitors. eFFECTOR received a $15 million upfront payment and is eligible for an additional potential of $492 million.
eIF4E (eukaryotic initiation factor 4E) is a highly oncogenic and historically intractable target whose expression is increased, or upregulated, in a variety of human cancers and is linked to poor prognosis and resistance to certain therapies. eIF4E selectively regulates the translation of a set of target mRNA distinct from those regulated by MNK1/2 and eIF4A. This may expand the potential patient population that may benefit from translation regulation therapy. We are completing IND-enabling studies for this program.