How a protein 'Polaroid' led Amgen to finally crack the 'Achilles heel tumor' with Lumakras in 8 years

Amgen
Scientists had been trying for decades to crack the code on the KRAS protein, theorizing that this “undruggable” target could be a breakthrough in cancer treatment. (Amgen U.K.)

For Amgen, Lumakras started with a Polaroid—well, a crystallographic image or X-ray of the molecular structure that makes up the KRAS protein. But for the sake of simplicity, a picture inspired the development of the soon-to-be blockbuster drug.

Then Amgen’s scientists hit the library. The drug library, that is.

Two of Amgen’s R&D and clinical development experts gave Fierce Biotech a snapshot into the light-speed development process that brought Lumakras, formerly known as sotorasib, to the cusp of an FDA approval in about eight years. The agency is considering an application for Lumakras under a breakthrough designation to treat non-small cell lung cancer in patients with a KRAS G12C mutation who have failed on several prior treatments.

“This has been a target of great desirability for many decades and so when we found that there was a potential way to address that, we did do things a little bit differently to go faster than we might have in the past,” said Amgen’s vice president of research, Margaret Chu-Moyer.

Scientists had been trying for decades to crack the code on the KRAS protein, theorizing that this “undruggable” target could be a breakthrough in cancer treatment.

It was a drug discovery team led by Chu-Moyer that finally got a foothold, nearly 60 years after the KRAS protein was discovered.

“For many decades it's been very hard to target, because KRAS protein itself is seen as this slippery protein. There's nowhere to hang on,” Chu-Moyer said.

Small molecules—drugs, to be clear—have to have a “foothold” on a protein to spur a pharmacological effect, she said. The breakthrough came in 2013 when the University of California, San Francisco’s Kevan Shokat, Ph.D., published that crystallographic image.

Gregory Friberg
Amgen's Greg Friberg (Amgen)

Amgen VP and Therapeutic Area Head, Oncology Greg Friberg calls it a “Polaroid of the protein.”

Chu-Moyer’s team noticed a little pocket on the protein that molecules could grab onto.

The KRAS protein has an on-off switch, essentially. When the protein is mutated, that active “on” switch proliferates “like crazy,” causing tumors to grow.

“What we've found is that you can actually lock the protein in the inactive state with a small molecule and turn it off,” Chu-Moyer said.

But Amgen still needed to find that molecule, so the team started doing what Chu-Moyer calls “submarine work” to build a library of potential covalent inhibitors that could prove to be potent against KRAS.

The next lightbulb moment for Amgen was when Araxes Pharma published a patent that provided direction on some structures that might work to create a novel molecule. From there, Chu-Moyer’s team was off to the races, she said. The result was AMG 510, which became sotorasib and now Lumakras.

“The baby was handed” to Friberg’s team to start the drug development process around 2018.

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By this point in oncology treatment, genetic sequencing of tumors was the norm, which helped Amgen quickly identify patients with the KRAS mutation that might respond to Lumakras. The phase 1 clinical trial got rolling quickly, which Friberg said is a testament to the speed at which drug development is now occurring.

“This is no longer the plundering creature that takes years and years to develop. When we see a drug that appears safe and effective, there are opportunities to move very quickly,” Friberg said. “We're sitting here now under three years since the first patient was dosed.”

Amgen found during the clinical trials that Lumakras could not only reduce tumors, but do so without harsh side effects. The effect was durable, too, which was backed up in study after study. So far, Amgen has recorded durability of 10 months.

“We're seeing partial responses or complete responses. We're seeing some patients whose tumors shrink away entirely,” Friberg said.

The FDA nod, should it arrive by August, will be just the beginning for Lumakras. Amgen wants, as is typical, to move the therapy up in line and offer it to patients earlier in their treatment journey. The company is examining different drug combinations in which the therapy might be useful as well as other tumor and cancer types that may respond.

But Friberg says all of this is being done carefully to ensure they understand fully the patients who might benefit the most from Lumakras.

Amgen is not the only player in the KRAS game, and Friberg and Chu-Moyer know it. The chief competitor is Mirati Therapeutics, which is bringing up a KRAS inhibitor called adagrasib behind Amgen. 

“One thing that's just absolutely true in science is that good ideas don't stay lonely for very long,” Friberg said. “We stood on the shoulders of giants and their work in what we were able to produce. Others are doing that as well and that's good for patients.”

RELATED: KRAS biotech Mirati delivers so-so news for investors closely watching Amgen battle

Amgen thinks its molecule—which is almost certain at this point to be the first on the market—will set the tone thanks to it’s once-daily oral administration and durability of response. It also has a unique binding mechanism, whereas Mirati’s has a different approach.

“It's good for there to be multiple opportunities to prosecute a given Achilles heel tumor,” Friberg said.

Another advantage for Amgen is it simply has the data, Chu-Moyer points out: “More options [are] better but you know, the proof is in the pudding.”

If every drug discovery journey could be as smooth as Lumakras, Friberg would be happy, and he hopes to be able to repeat the Lumakras timeline again someday. The molecule delivered to his team, however, was one of a kind, and the safety profile allowed them to move swiftly through the clinic.

“We move as fast as we can. Patients are waiting for these drugs, but we don't do so in a way that's arrogant with regards to the data that we're seeing,” he said. 

Friberg said a challenging part of developing Lumakras—even as fast as they managed to do so—is hearing from patients or their families who desperately need access to it. Amgen has had a compassionate use program that has provided early access, but the FDA approval will open the gates for everyone. 

"There are some patients who, unfortunately, have passed on before a molecule has been available. I think that's what hits me the most about speed. Even though we went fast, it was still too late for some," Chu-Moyer said.

Amgen did a few things differently—or at least in a way that was more risky than usual—that helped move things along. Chu-Moyer said they stepped up molecule assays to get data as fast as possible and began manufacturing large quantities of a finished product to prepare for launch.

Now that last part is industry standard and even a requirement, but Chu-Moyer and Friberg said this time around, Amgen did so at greater risk because of the short clinical timeline.

“The drug’s only been in the clinic for a year and you're starting to make quite a bit of supply. [It’s] a bit unheard of,” Friberg said.

The world saw this swift ramp-up and adoption of risk for pharmaceutical companies with the scale up of COVID-19 vaccines before they were authorized in 2020. The companies behind those shots—Pfizer-BioNTech, Moderna, Johnson & Johnson, AstraZeneca and others—manufactured huge quantities to be able to get as many of the billions of required doses to countries in need as fast as possible.

“It was pretty obvious to us that we thought we had a winner—things could have gone wrong—but we thought we had a drug that would offer patients something of value,” Friberg said.

The early ramp up was “not just a little risky … it was years of investment risk,” he added.

All of this allowed Amgen to go from “a twinkle in our eyes as to what molecule it might be, to today, in something like five years or so,” Chu-Moyer said.