One of the inconvenient truths of the biotech and pharmaceutical industry is that only about one out of every 10 drug candidates good enough to enter clinical trials passes all the tests to graduate as an FDA-approved therapy. Every major drugmaker is searching for ways to boost that success rate, and yesterday I got an interesting glimpse into how the world’s largest biotech, Amgen, thinks about how to raise its game.
Amgen is based in Thousand Oaks, CA, but has 900 employees in Seattle and about 200 more in Cambridge, MA, many of whom play critical roles in the perilous early steps of R&D where a lot of time and money get wasted. I got an overview from Amgen’s senior vice president of translational sciences, Joe Miletich, while he was in Seattle this week to meet with employees (and briefly enjoy the view of Elliott Bay from the office CEO Kevin Sharer sometimes uses).
Amgen (NASDAQ: AMGN) had $15 billion in revenues a year ago, largely from products for patients with anemia, autoimmune diseases, and cancer. About one-fifth of that revenue, $3 billion, was poured into the R&D budget. Much has been written about how Amgen coasted on the success of its first two blockbusters in the 1990s, acquired another one in 2002 from Seattle-based Immunex, but has more recently sought to re-ignite its innovation engine, particularly for cancer drugs, this decade under R&D boss Roger Perlmutter, a former Merck executive and University of Washington immunology professor.
Since it often takes a decade or more to develop a new drug, this effort is still a work in progress, but Amgen now has 50 drugs in the pipeline from the late discovery stage through Phase III clinical trials. Amgen has organized the pipeline with three key guys who report to Perlmutter from beginning to end. David Lacey runs the early discovery, Miletich handles translational steps from there through early-stage clinical trials, and Sean Harper is responsible for late-stage clinical trials.
Miletich was formerly a professor of internal medicine and pathology at Washington University in St. Louis and a Merck executive. His team in the middle of the R&D machine takes drugs after they’ve graduated from the discovery phase, and then runs them through a battery of genetic tests, cell-based tests, animal tests, models of disease, and biomarker studies to see which types of people might respond to such a treatment. The goal is to test whether the candidates are safe, and whether there’s “evidence of biological impact” that gives the company “a high degree of certainty” on whether the drug is actually hitting the desired target and doing what it is supposed to do in people, he says. If done right, this work is supposed to answer which of those 50 drugs on the roster, and which of the 6 to 8 new ones that enter human trials each year, are truly worthy of putting major-league resources behind in the ultimate proving grounds of Phase II and III clinical trials. The rest of the candidates, Miletich says, may need more long-term observation in people, while some should be killed early before too much money is wasted, he says.
This isn’t revolutionary stuff—it’s what other companies do, Miletich acknowledged. But it is an effort to weave together basic research and clinical development in a closer way than had been done in the past, when research might just hand over a drug to development to see if it worked, Miletich says. He says this more integrated, or “translational,” approach should pay off directly by raising Amgen’s success rate above the usual industry rule of thumb.
“Over the next five years, I’d like to see us have about a 20-30 percent higher success rate over the historical average,” Miletich says.
That sounded pretty bold, but Miletich was quick to throw in qualifiers.
There are apples-to-oranges comparisons when stacking up a low-risk program to develop another statin drug for lowering cholesterol, as opposed to a new drug for lupus, which uses a completely new mode of action for a disease that doesn’t have effective therapies. Amgen has been known in the past to take on some of these lower-risk projects, like making longer-lasting versions of erythropoietin (Aranesp) and pegfilgrastim (Neulasta). But now Amgen’s pipeline is a bit more daring, with about two-thirds to three-fourths of its candidates being aimed at diseases where no one has a marketed product that works the same way, Miletich says.
One of the most interesting examples that Miletich offered up is a new antibody drug emerging in Amgen’s pipeline, called AMG-785. This is based on biological work that says a protein called sclerostin normally neutralizes production of osteoblasts, the cells that build new bone. Some patients with rare genetic abnormalities, who lack the gene to make sclerostin, have been shown to end up with severe deformities from bone overgrowth by the time they are in their 30s, Miletich says.
Even more interestingly, patients with only one of two functioning copies of the sclerostin gene have no symptoms of disease, but they have really strong bone mineral density, which means they don’t develop osteoporosis later in life, and usually “they don’t break bones” in accidents, Miletich says.
So Amgen’s vision is to build on that fundamental genetic insight to create a drug that does that same thing, blocking sclerostin in a carefully calibrated way. With some clever in-house protein engineering, Miletich says Amgen showed an experimental antibody drug could block the correct functioning of the sclerostin protein and offer the desired bone cell-building effect in early stage studies. That drug, code-named AMG-785, is now one of the molecules that Amgen and its partner, Belgium-based UCB, are most excited about based on early studies that showed “a very robust response with a single injection,” Miletich says. The drug still has a lot to prove—it’s now in one Phase II trial and entering another—but it has forced its way to the top of Miletich’s priority list based on all indications from the early-stage studies.
There’s also a business case to be made for such a drug, and Miletich was no stranger to that. Nothing currently on the market for osteoporosis can build new bone. This product also dovetails nicely with the most visible drug in Amgen’s pipeline, denosumab. That product candidate, currently awaiting FDA approval, has been shown to lower fracture risk of patients through a different mechanism, stopping osteoclast cells from breaking down too much bone. That drug could generate $2.2 billion in annual sales by 2012, according to a Rodman & Renshaw analysis. Any new product that does the opposite—building up bone—could be given to patients with early-stage osteoporosis. Those patients could be brought back to a healthy state, and then put on denosumab therapy for “maintenance” to keep them healthy.
“This could give physicians and patients both sides of the lever,” Miletich says.
Whether that turns out to be true won’t be known until the late-stage clinical trials either prove or disprove what Miletich’s troops have done so far in their methodical quest to understand what the drug is doing at early stages. Even with a $3 billion research budget that can buy every state of the art tool, and recruit world-class scientists, Miletich made it clear this is still a very humbling industry.
“I don’t like to overhype things,” Miletich says. “All of us in the field do a disservice when we celebrate success in a way that comes out sounding like we’ve answered everything. That’s not true. Human biology is enormously complex.”