Pfizer and eFFECTOR Ink $507 Million Cancer Deal
Pfizer and eFFECTOR Therapeutics inked a global license and collaboration deal to develop small-molecule inhibitors of eukaryotic initiation factor 4E, also known as eIF4E. This factor is activity in a range of cancers and focuses on what is being dubbed the translatome—which is the area of cells where DNA is translated into proteins.
Under the terms of the deal, Pfizer will pay Effector $15 million up front. Effector will be eligible for a possible $492 million in research-and-development funds, and development and sales milestone payments, as well as potential royalties on sales of products that come out of the partnership.
“We look forward to working with Effector with the goal of bringing a promising new therapy to patients with various treatment-refractory cancers,” said Jeff Settleman, senior vice president and chief scientific officer, oncology, worldwide research, development & medical, for Pfizer.
eIF4E has remained an elusive target, despite several decades of interest. Eli Lilly and Ionis Pharmaceuticals, when Ionis was Isis, tried to move an eIF4E antisense molecule into the clinic in 2006. Other researchers worked on various molecules, such as hippuristanol, pateamine A and silvestrol, which affect other components of the eIF4E complex, including the eIF4E, but no one has made headway.
Effector and Pfizer hope to break that trend. Inhibitors of eIF4E act inside the tumor instead of on immunosuppressive factors in T-cells. eIF4E is toward the end of a process of protein manufacturing, after DNA has been transcribed and messenger RNA (mRNA) is prepared to be translated by ribosomes. eIF4E is important in actually launching the process of protein manufacture, and cancer cells depend on it to create what they use to supercharge their proliferation.
Theoretically, by focusing on the end of the pathway, you can treat a range of problems created by mutations earlier in the pathway.
“We believe that this agreement validates Effector’s pursuit of eIF4E, which has been a protein of interest for drug development for many years but has been very challenging to develop small molecules to target due to the nature of its binding side,” said Steve Worland, chief executive officer of Effector.
So far, Effector has zotatifin, an eIF4A inhibitor that entered Phase I/II testing in solid tumors in November 2019. It is enrolling patients with any KRAS mutation subtype or mutations, amplifications or fusions in HER2, ERBB3, FGFR1 or FGFR2 receptor tyrosine kinases. It also will evaluate patients with pancreatic adenocarcinoma with no molecular typing, since most of those cancers have a KRAS mutation.
“There is an immediate need for more effective treatment options in patients with advanced cancers unable to respond to alternative therapies,” Worland said at the time. “Tumors treated with agents targeting specific RTKs frequently become resistant, and there are no available therapies targeting multiple KRAS mutation subtypes. The antitumor response observed in preclinical studies demonstrates the potential for zotatifin in the treatment of solid tumors with genetic modifications associated with aggressive disease, including RTK alterations such as FGFR1/2 and HER2 and KRAS, and provides direction for patient selection in our clinical trial.”
Zotatifin is a selective inhibitor of eIF4A, which is located downstream of various key oncogenic mutations and their resistance mechanisms. As such, zotatifin appears to inhibit the translation of mRNA that encodes several important oncogenes and cancer survival factors, including RTKS, KRAS, Cyclin D, MCL1 and BCL-2. It has the potential for use in the treatment of a variety of cancers, including colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B-cell lymphomas.