Lirafugratinib (formerly RLY-4008) was designed to selectively inhibit FGFR2 proteins in solid tumor cancers while sparing similar-looking proteins in the FGFR family. Relay Therapeutics and D.E. Shaw Research used the Anton 2 supercomputer architecture to conduct long-timescale molecular dynamics simulations to predict subtle but important differences between a flap on FGFR2 and FGFR1, allowing researchers to design a chemical compound that attached into a binding pocket on the target, but not related proteins.

Although several drugs are approved in the United States for FGFR-altered cancers, they also inhibit FGFR1 (causing elevated blood levels of phosphate) and FGFR4 (causing diarrhea). They're selective for FGFR proteins, but not the FGFR2 protein.

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Improved tolerability can also lead to improved efficacy. Lytgobi, the best-performing drug approved for FGFR-altered cancers, demonstrated an objective response rate (ORR) of 42% in its pivotal study. An objective response measures how many individuals saw their primary tumors shrink in size by at least 30%. Lirafugratinib notched an ORR of 82% in its pivotal study for the same tumor type.

The U.S. Food and Drug Administration (FDA) will consider the data for approval in CCA, but regulators wanted the company to conduct a larger study to collect more data in the tumor-agnostic treatment setting (meaning non-CCA tumors harboring an FGFR2 alteration). The initial opportunity is too small to justify the build out of commercial infrastructure for Relay Therapeutics, especially considering the focus on the significantly more valuable HR+/HER2- breast cancer portfolio. There are roughly 650 new cases of CCA in the United States each year (1,400 globally), although the tumor-agnostic opportunity spans an estimated 4,000 new diagnoses (13,000 globally).

As a result, the company intends to find a global commercialization partner for lirafugratinib. Such a monetization transaction could yield a meaningful upfront cash payment of $50 million to $100 million, plus larger milestones due pending developments in the tumor-agnostic opportunity.