Amgen's never moved faster.
In late August of last year, the first patient enrolled in a small clinical study received treatment with a cancer drug now known as AMG 510. Just over nine months later, Amgen executives were at oncology's premier annual meeting presenting results from the Phase 1 portion of testing.
"The time between those two major milestones was by far the fastest in our organization," said Sanket Agrawal, head of the AMG 510 program, in an interview with BioPharma Dive.
The drug's target, an oncogene called KRAS, has for decades proved unassailable to the industry's best efforts at countering its tumor-boosting effects.
Clinical results presented by Amgen in June, while preliminary, were the most promising to emerge since researchers first identified KRAS in the 1980s. Among 10 lung cancer patients, five saw their tumors shrink, including all three who received the highest dose, which Amgen is now advancing into Phase 2 testing.
"This target is the white whale of drug development," said Agrawal, who's worked at Amgen nearly 10 years. "We finally have a harpoon in its back."
Doctors and analysts interviewed by BioPharma Dive are also optimistic, although cautioned more data is needed to determine whether the promising responses presented in June hold up over time and across more patients.
"Five out of 10 is a pretty small number," said Roy Herbst, chief of medical oncology at the Yale Cancer Center, in a June interview. "If you want to say something really has a 50% response rate, you should have 30 or 40 patients to have some precision behind that measurement."
AMG 510's potential will become clearer soon. Amgen plans to disclose updated results at the World Conference on Lung Cancer in September and again at the European Society of Medical Oncology's annual meeting — making the next few months "the most important fall" the biotech has had in years, according to Cantor Fitzgerald analyst Alethia Young.
If the updates are similarly positive, Wall Street's pencil estimates of a billion-dollar market for AMG 510 might look a bit more real, and Amgen's cancer push more formidable.
A 'Navy Seals' team
Founded in 1980, Amgen now ranks among the top 10 drugmakers by market value and in many respects appears more a large pharma than its more nimble biotech beginnings.
In assembling researchers to push AMG 510 forward, though, Amgen sought to recreate a "biotech within a large company," said Agrawal.
Researchers on the project, many of whom have been with the company between five and 10 years, are set up in their own wing of an Amgen research facility — ring-fenced from the rest of the organization geographically as well as organizationally.
"At a large organization, one of the challenges when we get too set in our ways is we have a machinery around us," added Greg Friberg, Amgen's head of global development, in an interview.
The goal, according to Friberg and Agrawal, is to hasten AMG 510's development and consider earlier the regulatory affairs, commercial and manufacturing issues that typically follow initial testing in humans.
While early-stage programs are usually relegated to bulleted updates in corporate slide presentations, Amgen's top executives have got out in front of investors to talk up AMG 510 sooner than might be expected for a Phase 1 drug.
"We have what I characterize as a Navy Seals team."
Head of R&D, Amgen
"Within precision oncology, we said we are going to go after very high value targets: KRAS, MCL-1, 'Holy Grail'-type targets," said R&D chief David Reese, speaking at healthcare conference held by Goldman Sachs in June days after presentation of the initial AMG 510 results.
"We are not a chemistry organization of 3,000 individuals, but we have what I characterize as a Navy Seals team there."
Amgen's not alone in making a bet on precision oncology. It's an area that's seen a surge in investment as improved medicinal chemistry has opened up new therapeutic opportunities.
"The ability to predict and develop drugs that will bind to difficult targets has improved dramatically," said Tyler Van Buren, a biotech equities analyst at Piper Jaffray, in an interview.
"We've seen this across the precision medicine oncology space. Look at Loxo, Array, Blueprint or Deciphera," he added, referring to several biotech developers of targeted cancer therapies.
That quickening pace of research has spread to KRAS too, even with its track record as an elusive target. Now, AMG 510 headlines a wave of experimental therapies just beginning to enter clinical testing.
A wave of new KRAS efforts enters the clinic
|AMG 510||Amgen||5/10 responses in NSCLC, updated data due Sept. 8|
|MRTX849||Mirati Therapeutics||Initial data expected in October|
|mRNA-5671||Moderna, Merck & Co.||First patient dosed in Phase 1|
|KRAS TCR||NCI, Gilead||Phase 1 study begun in May|
|"SLATE"||Gritstone Oncology||First patient dosed in August|
|AZD4785||AstraZeneca, Ionis||Discontinued after Phase 1|
|ARS-1620, -3248||Wellspring, Johnson & Johnson||Preclinical development|
SOURCE: Companies, clinicaltrials.gov
AMG 510 targets a specific mutant form of KRAS called G12C that's present, according to numbers cited by Amgen, in roughly 13% of all lung cancers, as well as between 1% and 3% of other solid tumors. (All told KRAS mutations, including G12C, G12D and G12V, are found in about 30% of lung cancers.)
By comparison, ALK mutations occur in lung cancer about one-fourth as frequently. Sales of two approved ALK inhibitors, Roche's Alecensa and Pfizer's Xalkori, are currently annualizing at about $1.4 billion — giving some sense of the market opportunity Amgen's chasing with KRAS.
Past attempts to target KRAS failed to effectively bind a small molecule drug to the desired target. Amgen says it's solved this by taking aim at an amino acid in what Friberg dubs a "hidden groove," an approach laid out in a 2013 paper from researchers at the University of San Francisco, California.
When AMG 510 locks onto that groove, the drug irreversibly inactivates the mutant KRAS protein and thereby mutes signaling that directs tumor growth.
Michael Yee, an analyst at Jefferies, estimates Amgen is about six months ahead of its competition, which are following a variety of paths to attacking KRAS.
Mirati Therapeutics is set to read out initial findings next, with clinical data for its compound MRTX849 due this fall. Johnson & Johnson looks to be one to watch as well, having inked an exclusive collaboration with a company tied to the UCSF researchers.
A home-grown success?
Amgen's position out at front in targeted oncology research is new.
The Thousand Oaks, California-based drugmaker does sell a number of cancer drugs — including the myeloma treatment Kyprolis and the chemotherapy Vectibix — but it's known more for its inflammatory disease and supportive care products.
(Neulasta and Neupogen, for instance, are bone marrow stimulants that can help people following cancer treatment.)
The cancer therapeutics it does sell came mostly by way of acquisition, through buyouts of Abgenix, Onyx, Micromet and BioVex, and have had mixed commercial success.
Cancer drugs Amgen's acquired
|Drug||Acquired via (Deal amount)||Year of deal||2018 sales (millions)|
|Vectibix||Abgenix ($2.2 billion)||2006||$671|
|Imlygic||BioVex ($425 million)||2011||Not disclosed|
|Blincyto||Micromet ($1.16 billion)||2012||$230|
|Kyprolis||Onyx ($9.7 billion)||2013||$968|
SOURCE: Company statements
Its research efforts in-house, meanwhile, have resulted in a number of late-stage misses. Between 2011 and 2015, Amgen discontinued or out-licensed four late-stage cancer drugs developed by its own labs: motesanib in lung cancer, ganitumab in pancreatic, rilotumab in gastric and trebananib in ovarian.
"510 is the crown jewel in a plan that really was to try to commercialize multiple products in oncology," said Friberg.
"We've never gone away, but people typically think of us more as a supportive care company because of the way that some of the cards that we've turned over [during] the last decade have played out."
Amgen's betting the next decade will look differently. While its mid- to late-stage cancer trials are in support of already-approved products, the biotech has 15 programs now in Phase 1.
"They are not here to have one drug. They are here to build an oncology platform pipeline," said Cantor's Young.
AMG 510 is the highest profile of those efforts, but expectations are now at risk of outstripping the data Amgen's to date disclosed. If subsequent updates next month and after fall short, optimism could unravel.
For SVB Leerink analyst Geoffrey Porges the potential to drug KRAS is part of what he dubs "the new Amgen — flat revenue, promising pipeline, nervous investors."