The first public glimpse of data from a mid-stage clinical trial of Bristol and Alder’s experimental antibody drug for rheumatoid arthritis appeared online last week. These are the results from a 124-patient clinical trial coming up next month at the European League Against Rheumatism (EULAR) conference in Barcelona. The drug’s ability to relieve signs and symptoms of rheumatoid arthritis are “outstanding” and “certainly as good” as its competitors, according to lead investigator Philip Mease of Swedish Medical Center and the University of Washington.
Before delving into the nitty gritty of the study, here’s a little background. Back in November, Bristol agreed to pay Alder as much as $1 billion over time for the right to co-develop a new antibody drug for patients with rheumatoid arthritis, called ALD518. Alder CEO Randy Schatzman said at the time that he had data from a rigorous clinical trial that said his drug was good enough to give the category-leading biotech treatment, Amgen’s etanercept (Enbrel), a “run for their money.”
The Alder drug is designed to work differently than the Amgen product. Alder is seeking to block an inflammatory protein called IL-6 that hammers the joints of rheumatoid arthritis patients, causing swelling, fatigue, and pain. The Amgen product and others like it—which make up a market worth more than $10 billion a year—work toward the same goal by hitting a different inflammatory protein called TNF. Rheumatoid arthritis is estimated to affect at least 2 million people in the U.S. in at least a mild to moderate degree. About one-third or more of patients don’t benefit at all from the TNF-blockers, and scientists don’t really know why, so there’s impetus for therapies with different ways of working. Plus, Alder’s drug can be made in a faster, cheaper, yeast-based production system that could allow it to undercut rivals on price while maintaining fat profit margins. (The Alder drug is thought to have potential for cancer as well, but that’s another story).
So this definitely matters from a business perspective, but what did scientists learn from this study? Patients with rheumatoid arthritis took methotrexate, and were randomly assigned to get either a placebo or a low, medium, or high dose of ALD518 given intravenously every eight weeks. Patients were followed for 16 weeks. Over that relatively short period of time for people with a chronic disease, the drug was considered safe. No patients suffered infections, and none had adverse immune reactions against the drug as a foreign invader. About 17 percent of ALD518 patients had increased amounts of liver enzymes showing up in their blood, which can be a sign of liver damage that the FDA keeps a close eye on.
What’s really interesting, though, is the data on effectiveness. It’s easiest to put this in a table below, but it warrants a little explanation for those unfamiliar with rheumatoid arthritis. Doctors who specialize in this condition generally want to see how many patients on a drug can see at least a 50 percent improvement in the signs and symptoms of their disease. That’s called an ACR50 score, for a standard composite measurement used by the American College of Rheumatology. There’s another measurement, called ACR70, which is for the number of patients who had at least a 70 percent improvement in the signs of symptoms of their disease.
If you look closely at the chart below, you’ll see patterns that scientists (and drug makers) really like to see. The higher the dose that patients got, the greater the chances were that they’d improve—what’s known as a dose-response relationship. And the longer patients stayed on the drug, the better they performed. The Alder drug clearly beat the placebo in every category, and the difference was statistically significant, meaning it wasn’t likely to be a fluke. At the highest dose of the Alder drug, you can see that half of all patients saw a 50 percent or greater improvement in their condition after 16 weeks.
|Week 4||80 mg||160 mg||320 mg||Placebo|
|ACR50||9 percent||15 percent||29 percent||3 percent|
|ACR70||6 percent||0||11 percent||0|
|Week 16||80 mg||160 mg||320 mg||Placebo|
|ACR50||41 percent||41 percent||50 percent||15 percent|
|ACR70||22 percent||18 percent||43 percent||6 percent|
Alder is limited in what it can say in advance of the meeting, but Schatzman said, “It’s a good start. We’re pretty enthusiastic.”
OK, but how does this compare with the gold standard biotech drug from Amgen? I must say this isn’t a totally valid comparison, because this wasn’t a head-to-head study of Amgen versus Alder, and there are always different variables that make it difficult to compare one clinical trial with another.
But to get an idea of how strong the Alder data are, I looked at the FDA-approved prescribing information for the Amgen drug. As you can see in the table below, the Amgen drug showed in what it calls Study 1 that can help about 40 percent of patients get to that same benchmark of effectiveness, after a longer period of treatment—six months. To be fair though, the Amgen drug has been around since 1998, and has reams of long-term data to show that it is safe and effective over the long haul, and even can help halt progressive joint damage.
|Month 3||Enbrel 25 mg twice-weekly||Placebo|
|ACR50||41 percent||8 percent|
|ACR70||15 percent||4 percent|
|Month 6||Enbrel 25 mg twice-weekly||Placebo|
|ACR50||40 percent||5 percent|
|ACR70||15 percent||1 percent|
And there are definitely caveats in the Alder data that must be pointed out. First, the Alder drug was given in an IV formulation every eight weeks, meaning that patients had to come in to see the doctor. That’s not really competitive with drugs from Amgen and Abbott Laboratories, which patients can give via self-administered injections just under the skin. So Alder and Bristol are reformulating ALD518 into a more convenient and competitive package, in what is known as a subcutaneous form. That’s the version that Alder and Bristol will need to take into a pivotal, Phase III clinical trial in many more patients, which the FDA will want to see before it will consider clearing the Alder drug for sale in the U.S. The pivotal trial will also have to be longer, following FDA guidelines that ask for six months of observation, Schatzman says.
“This was a small study, really a scientific proof of principle,” Schatzman says. “We need to do a much larger trial and see whether we can repeat the results.”
Mease, who has a lot of experience studying the other rheumatoid arthritis drugs, says that the Alder results are still early. Still, the results thus far are “certainly as good as any early anti-TNF data,” Mease said in an e-mail. “Significant development program from [Bristol-Myers Squibb] is to follow.”
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