Pipeline
of Selective Translation Regulator Inhibitors
Program
(Target)
Discovery
Preclinical
Phase 1
Phase 2
tomivosertib
(MNK1/2)
Combination
Indication | NSCLC – 1L Extension in combo with pembro
Indication | NSCLC – 1L in combo with pembro
Indication | mBC – SU2C combination trial*
zotatifin
(elF4A)
Indication | Solid Tumors RTK BC and KRAS NSCLC
Indication | Anti-SARS-CoV-2 Dose Escalation
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 prolonged sensitivity to checkpoint inhibitors and longer progression free survival (PFS). In addition, our preclinical data demonstrate that tomivosertib as a single agent promotes antitumor immunity that persists after stopping drug treatment.
We recently initiated the KICKSTART study, a randomized, double blind, placebo controlled Phase 2b study in patients with first line metastatic non-small cell lung cancer (NSCLC) with PD-L1 expression ≥ 50%, combining tomivosertib with pembrolizumab. KICKSTART will include two cohorts; patients who are treatment naïve and patients who have experienced an initial RECIST progression on pembrolizumab monotherapy. Both cohorts will be randomized 1:1 to tomivosertib + pembrolizumab or placebo + pembrolizumab. Previously we completed a 39 patient Phase 2a trial with tomivosertib in combination with checkpoint inhibitors. Tomivosertib is also being studied in combination with paclitaxel to treat patients with metastatic breast cancer in a 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 at the bottom of both the RAS and PI3K signaling pathways. We have demonstrated that eIF4A inhibition selectively regulates the translation of a distinct set of target “onco”mRNA that include a number of important oncoproteins and survival factors, including – certain receptor tyrosine kinases (RTKs) such as EGFR, HER2 and FGFR 1/2, KRAS (independent of mutation subtype), and cell cycle proteins including Myc, 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 are currently evaluating zotatifin in a Phase 1 dose escalation clinical trial in solid tumors, and we plan to initiate P2a expansion cohorts in the second half of 2021.
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, subject to achieving certain clinical, regulatory and sales milestones.
eIF4E (eukaryotic initiation factor 4E) is an oncogene 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. Pfizer is currently conducting IND-enabling studies for this program.