Eli Lilly is rejoining the KRAS hunt.
The Indianapolis Big Pharma revealed Thursday, in an abstract for AACR, that it has been working on a new small molecule to target the infamous oncogene and are planning to put it into Phase I later this year. It marks Lilly’s first public foray into the field in nearly a year, since it ditched its first molecule after seeing dangerous side effects in five patients.
The new abstract opens with a public diss. Like the old molecule, Lilly’s new candidate goes after KRASG12C, the same mutation that Amgen and Mirati have targeted in their late-stage programs. Those may be on a path to approval but, Lilly said, they’re pretty weak drugs.
“Currently, there are no FDA-approved KRAS-G12C inhibitors,” the company’s researchers wrote, “and those in clinical development have relatively modest activity compared to other approved therapies targeting other classic oncogenic drivers.”
There are data to bear the claim out: Although doctors and scientists have wanted a KRAS drug for decades, only about 30% to 40% of lung cancer patients with the mutation respond to Amgen and Mirati’s drugs and their tumors only stop growing for about 6 to 7 months.
That may help thousands of patients in the next decade, but it falls short of the effect seen in other targeted lung cancer drugs. The drug has hardly worked at all on other tumor types.
Lilly’s scientists attributed the meh response seen in many patients in part to molecules that don’t completely fill the target pocket on KRASG12C. They claimed their drug was much better at doing so. It’s over 25 times more potent than Amgen’s, they wrote: You need 3.35 nanomolars of the Lilly molecule to reduce the protein’s activity by 50%, compared with 89.9 nanomolars of the Amgen molecule. You need 47.9 nanomolars of Mirati’s molecule.
They will have the chance to prove that difference translates into the clinic later this year. The researchers noted, though, what Amgen and Mirati’s clinical data have already borne out: Not every tumor is equally dependent on KRAS and, for many, a combination approach might be necessary.