There are a lot of radical ideas for treating cancer, and most are pure bunk. But now one of Seattle’s most promising biotech startups, Alder Biopharmaceuticals, says it has the first hard evidence to support a concept that would have gotten them laughed out of the room by most cancer physicians a year ago.
Alder’s big idea is to treat cancer without fighting the tumor. And even without shrinking tumors or keeping them from spreading, the company now says it has evidence that suggests its drug will help cancer patients live longer, and enjoy a higher quality of life. The first glimpse of solid data to back this up, from a 124-patient study of cancer patients who got Alder’s experimental drug or a placebo, is coming out next month on the biggest stage in the world of cancer drug development, the American Society of Clinical Oncology’s annual meeting.
“When we got our first data and proposed this study, we ran into oncologists who said, ‘If you’re not killing the tumor, we’re not interested,'” says Randy Schatzman, Alder’s co-founder and CEO. “But then we talked to others who said it’s really nice to have something that treats the patient, not the tumor.”
Alder comes from humble beginnings as a true bootstrapped company, and it first rose to national prominence last November. That’s when pharmaceutical giant Bristol-Myers Squibb agreed to pay Alder as much as $1 billion over time for the right to co-develop the small company’s experimental antibody drug for rheumatoid arthritis. The drug is so highly prized because it is made in a yeast-based manufacturing system that is much faster and cheaper than the traditional approach, which makes biotech drugs in mammalian cells. Roche has already proven that it can win FDA approval for a new drug that hits an inflammatory protein known as IL-6, which is the same molecule that Alder is seeking to tamp down with what it considers a better, faster, cheaper alternative.
What few people realized about that deal at the time is that Alder retained 100 percent global ownership rights to the same drug that targets IL-6, ALD518, for use as a cancer therapy. Research has been pouring out of academia for years that shows how excess inflammation from proteins like IL-6 is what Schatzman calls “the true villain” that really kills people who have cancer. About one-third of cancer patients suffer from cachexia (pronounced Kuh-KECK-see-uh), which is extreme fatigue and muscle atrophy that comes from inflammatory overdrive. Doctors can give patients generic immune-suppressors, but they are blunt instruments that have unwanted side effects. Most of the time doctors are so concerned about the tumors, they don’t bother to treat the inflammation that makes people feel miserable.
Regardless of what the X-rays or CT scans might say about how well chemotherapy is doing to shrink tumors, the extreme fatigue of cachexia causes patients to lose weight, lie in bed, get depressed, and basically waste away until they die. “Eventually, a lot of people sort of lose the will to live,” says Mark Litton, Alder’s chief business officer.
The concept is that ALD518, given in an intravenous infusion, will specifically latch onto the excess IL-6 inflammatory molecules and neutralize them. Since overactive inflammation consumes extraordinary amounts of energy—if you’ve had the flu, you know what I mean—then it stands to reason that if you tamp down excess inflammation, people will feel more vigorous. For a cancer patient, that could mean the difference between being bedridden or able to walk around or climb stairs. Taken a step further, a more vigorous patient might be able to withstand higher doses of chemotherapy or further rounds of anti-tumor drugs, rather than go home to die.
Alder tested this original hypothesis in a small study, to assess safety, in nine patients. The first batch of results were presented at last year’s ASCO conference. The Alder drug was found safe in three different doses of an intravenous infusion. There also were a couple anecdotal cases of patients who were bedridden and waiting to die who were able to get out of bed after infusion. They regained weight and resumed chemotherapy, Schatzman says.
It would be hard to overstate how radical an idea this is to the world of oncology and to the FDA. There is only one gold standard measurement for success in cancer drug development, and that’s whether a drug can help people live longer. Given the time and expense it takes to demonstrate that in a clinical trial, the FDA and cancer experts will sometimes be satisfied with leading indicators of success, like whether a new drug can keep tumors from spreading through the body for a longer time than the standard of care, or whether it does a better job of shrinking tumors. While cancer drugmakers often ask patients in clinical trials to fill out questionnaires about their quality of life, that’s generally considered a mushier, subjective measurement that would never be sufficient evidence to win FDA approval.
Alder knows exactly what it is up against, in terms of the conventional wisdom of cancer physicians and the FDA. But Schatzman says the data that Alder has in hand from a more ambitious mid-stage trial of 124-patients is compelling enough that his team is in the midst of designing a pivotal clinical trial of ALD518 that could show the drug improves quality of life, and helps people live longer. Alder hasn’t finalized the design of this study, but Alder is preparing to budget $50 million of its own money on this trial.
“We could change how physicians view cancer, and change the treatment of it,” Schatzman says.
Some data from Alder’s cancer study will first dribble out in public at 3 pm Pacific time on May 20 when ASCO publishes the abstracts of presentations in advance of its full conference from June 4-8. But here’s what I was able to gather about this trial from the public record, and Schatzman.
The Alder cancer study enrolled 124 patients who had terminal forms of non-small cell lung cancer, and who were so sick they had lost at least 5 percent of their body weight and gone off their chemotherapy. Patients were randomly assigned to get a low, medium, or high dose of the Alder intravenous drug every eight weeks, or a placebo infusion. Researchers followed the patients for about six months to see how they did.
The main goal of the study was safety, not efficacy. But Alder designed the trial with enough patients enrolled to demonstrate a statistically significant benefit on some key secondary questions. Those questions were whether patients on ALD518 were able to maintain or gain weight, how much strength they had for a hand grip test, how well they scored on a common fatigue questionnaire known as SF-36, and a measurement of their thrombotic tendency. That last question is important, because markers of inflammation are thought to break lose clots (thrombus), which have a tendency to cause trouble like heart attacks and strokes. Many cancer patients actually are thought to die because their red-hot inflammation rips loose a clot that leads to a fatal stroke or heart attack, Schatzman says.
Importantly, the trial wasn’t designed to ask whether ALD518 shrinks tumors, like most trials.
While Alder isn’t disclosing the results, Schatzman did tell me that Alder’s drug showed advantages over a placebo on all the scores, and they were statistically significant. Since Alder wants to unveil the details in a proper scientific forum with a lot of influential cancer physicians in the audience, we will all have to wait and see the actual results at the ASCO conference.
Still, the data is compelling enough for Alder to plot its next steps. The company is working on a lower-dose IV formulation of ALD518 that can be given every three weeks, so it can be given conveniently on the same schedule on which many cancer patients get their chemo infusions. Alder is working to pick the right patient population, and the right questions to ask in the study so the company can impress physicians and the FDA that it truly has a winner. The trial coming up at next month’s ASCO isn’t offering anywhere near enough proof, and Alder knows it. “We’re trying to move forward in a stepwise fashion.”
Mark Monane, an analyst with Needham & Company and an MD trained in geriatric medicine, told me last month at a Seattle investor conference that he was intrigued by Alder’s cancer-fighting approach. Monane has been following cancer companies like Seattle-based Dendreon for more than a decade, and knows that company’s appeal is deeply rooted not just in a cancer drug that helps people live longer, but that is based heavily on improved quality of life.
“Cancer cachexia is a real problem,” Monane said. “We focus a lot on drugs that kill tumors, but not as much on actually helping the patient. This is something that can help the patient, and you can get an answer on that relatively quickly.”
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