Eyeing the 'translatome,' Pfizer ties another knot with biotech partner for preclinical, next-gen targeted therapies
After closely following eFFECTOR Therapeutics’ work on next-gen targeted cancer therapies in the past two years, chipping in its own venture dollars and inking an I/O combo collaboration with its PD-L1, Pfizer is betting on a second drug candidate from the biotech partner.
The preclinical deal starts relatively small — $15 million upfront — but Pfizer has committed to $492 million in R&D funding and milestones, as well as royalties and an option to co-promote in the US.
With Pfizer shouldering some responsibility, eFFECTOR can now devote more of its resources and time to the clinical development of its lead program, CEO Steve Worland told Endpoints News.
The pact centers around eukaryotic initiation factor 4E, or eIF4E. Like MNK — the target of eFFECTOR’s lead therapy tomivosertib (formerly eFT508) — eIF4E is part of the PI3k/AKT/mTOR and RAS oncogenic pathways. Unlike tomivosertib, though, eIF4E inhibitors are designed to act within the tumor rather than immunosuppressive factors in T cells.
Sitting near the end of the whole process of making proteins — after DNA has been transcribed, with the mRNA ready to be translated by ribosomes — eIF4E is instrumental in actually kicking off the process of making proteins. Cancer cells rely on this mechanism to create what they need to proliferate; in fact, the translation component gets turbocharged, Worland said.
Hitting the end of that whole process also means targeting where multiple mutated genes and receptors converge.
“So if you’re downstream, you may collect a set of different mutations that all activate your target; any one of those mutations can confer sensitivity,” he said.
By focusing on the “translatome,” Worland added, eFFECTOR also hopes to circumvent the feedback loops in which tumor cells sense that one pathway has been blocked and quickly switch to an alternative.
“That was the origin of the company, really, looking at targeted therapies and high response rates, but unfortunately sometimes short durability of response, and thinking: how can we think about the pathways and find the points where you aren’t necessarily susceptible to those resistance mechanisms?” he said. “So we consciously chose to go downstream of the oncogenes (and target) the effector complex.”
The discovery program is now in a relatively mature stage, according to Worland, having devoted much effort in moving from a natural ligand that’s “lightyears from druglike space” to an orally available therapy that fits into the binding site.
Jeff Settleman, Pfizer’s chief scientific officer in oncology, highlighted its promise for patients with various treatment-refractory cancers.
The two partners are continuing to test eFFECTOR’s MNK1/2 inhibitor tomivosertib with Pfizer/Merck KGaA’s Bavencio. Preliminary data from a Phase I/II study presented at ASCO suggested that “the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity.”