What FDA 'interchangeability' means for Humira
The FDA recently designated Yuflyma as "interchangeable" with the popular biologic Humira for the treatment of Crohn's disease and ulcerative colitis, two types of inflammatory bowel disease (IBD), and a host of other illnesses. It was the fourth biosimilar to be designated interchangeable with Humira, after Cyltezo, Simlandi, and Abrilada.
Biologic drugs are medications made from living cells. Humira is a biologic that works by blocking a protein that causes inflammation. It treats many conditions, including IBD, rheumatoid arthritis, and psoriasis.
Biosimilar drugs are copies of biologic drugs, typically made after the original patent expires. Makers of biosimilars must prove to the FDA that they work just as well and are just as safe as the original drug.
Russell Cohen, MD, a professor of medicine at the University of Chicago and clinical director of the school's Inflammatory Bowel Disease Center, sat down with WebMD to explain how interchangeability works, how effective biosimilar drugs like Yuflyma can be, and what it all means for patients with a range of inflammatory conditions.
What is interchangeability, and why does the FDA grant it to certain biosimilars?
The originator drug (Humira) has the patent. When the patent expires or when one of the biosimilar companies challenges the patent, they undergo extensive testing to prove to the FDA there's no clinically meaningful difference in safety or efficacy between them and the original drug.
Typically, in cases of inflammatory bowel disease, the biosimilars usually don't test in those diseases. They are usually tested in the (related) disease states of psoriasis and/or rheumatoid arthritis. It's much easier to look at those disease outcomes, rather than sending someone to a colonoscopy.
By FDA standards, interchangeability means there's been additional testing in one of those disease states and they've shown the patient can be moved back and forth multiple times between the originator and the biosimilar and still fulfill the requirements for safety and efficacy. Even if you're going back and forth, the body doesn't seem to recognize it as being any different and doesn't show problems with immunogenicity (a drug's tendency to trigger an unwanted immune response).
After they do the testing, let's say for both rheumatoid arthritis and psoriasis, they ask for "extrapolation" to the other disease states (such as IBD) that the original drug already has FDA approval for.
How do biosimilars differ from conventional drugs, particularly in terms of replication?
Biologics are very expensive to make, because they're biological products. They're made through techniques where you have to insert the DNA or RNA for the particular protein you want to make – adalimumab (Humira), infliximab (Remicade), whatever – into cells, usually Chinese hamster ovarian tumor cells. These tumor cell lines pump out tons of protein, and so the protein is adalimumab. Then, they go through the purification and make sure there's no bacteria, no viruses. It's expensive.
Humira underwent very expensive, large trials. It takes years for the drug to get to market, and a ton of the money is spent on proving Humira works on a certain condition, right?
With biosimilars, you don't have to go through huge clinical trials. You have to prove your biosimilar has no clinically relevant difference in efficacy, purity, immunogenicity, or safety than the brand-name Humira. They're never going to be exactly the same, but they're so similar that the differences are not felt to impact efficacy or safety or immunogenicity. … In fact, they can't work better than the originator. If they do, they're not a biosimilar. They have to be not better and not worse.
But not all biosimilars are interchangeable with the originators?
No. Initially, none were, but subsequently with additional testing – again, back and forth – some of them have achieved interchangeability, and it's a designation by the FDA. Basically, the pharmacists can give whatever one they want, if it's [an interchangeable] biosimilar, without my permission, and the notification is based on state laws.
How does one biologic treat illnesses ranging from Crohn's and UC to psoriasis and rheumatoid arthritis?
Through years of investigations, researchers have discovered certain inflammatory proteins that the body's white blood cells or other cells make that cause the inflammation. Why does it start? By some type of stimulus – maybe a bad meal, a virus, maybe major stress – some stimulus where the immune system, which is probably genetically predisposed, triggers "on." You have certain cells that start producing chemicals and stimulate the white blood cells and other cells. Your white blood cells are your Army. Other cells are like the Marines. Some are like the National Guard. They get the signal – Paul Revere, right? – that there's an invader in sector colon or sector joint or sector skin. "Bring in the white blood cells and get rid of it."
The chemical messenger behind the first successful monoclonal antibody biologic for inflammatory diseases, infliximab, and most others for the first decade or so, is TNF-alpha, tumor necrosis factor alpha, which has nothing to do with tumors. It's a potent inflammatory protein your body makes. The levels are very high in people with active Crohn's, colitis, rheumatoid arthritis, psoriasis. Drugs like Remicade and Humira basically target TNF-alpha. You want to decrease as much as possible the TNF-alpha in the body.
Are there differences between Humira and interchangeable biosimilars such as Yuflyma that patients should understand?
Patients should be, I think, reassured that an FDA-approved biosimilar should, in most cases, perform as well as the originator drug. While there are some patients who change to a biosimilar or change to the originator and seem to get worse, there's also something called the "nocebo effect." Different than the placebo effect, the nocebo effect is, "Hey, I'm doing great on this drug, and then you changed me to a different one, and now I'm doing worse because you changed me." Usually, that's not the reason.
Sometimes there are cases like that, but when they change people in clinical studies, they blindly change them. They say to everyone, "OK, some of you are going to switch to the biosimilar, some of you can stay on the originator," but you don't know and they seem to work the same, right? Occasionally, there are patients who have a reaction. Maybe there's something else in the process – how it was made, things like that – but usually it should be fine.
With Humira and the biosimilars – and now with Stelara and the biosimilars – it's a different injector. The needle is a little different. Some people like the injector on some of the biosimilars better than Humira, so I'm not saying it's necessarily bad. It is different.
One thing they should be aware of is that the original Humira contained citrate, a preservative. It can burn with a shot. Many patients moved to the citrate-free Humira, so we want to make sure that the biosimilar they get is also citrate-free. Not all of them are.
Another issue that's important: Many patients on commercial insurance get some type of assistance for their, let's say, Humira, through the manufacturer. You may be able to get your medicine for $5 or less. Depending on the patient's insurance, the company can supplement what the patient needs to pay after their insurance kicks in a certain amount. Doctors need to make sure that that's going to happen with the biosimilar medicine that they're changing to. The idea behind biosimilars is really to expand the availability of what were very expensive drugs. In Europe, biosimilars have really brought down the price of the drugs. But in the United States, things are much more complicated.
Humira can cost up to $85,000 a year without insurance or assistance, where some biosimilars can be acquired for $12,000 annually. Do biosimilars and interchangeability always save patients money?
One criticism of the initial infliximab biosimilar was they came in too high and (Remicade maker Johnson & Johnson) was able to match their cost or they used discounts, rebates. Rebates are complicated. They are negotiated. Believe it or not, with some of the IV ones like infliximab, sometimes there's a high-cost one and a low-cost one.
Depending on how the patient's insurance works, the insurance chooses which one they want. In general, biosimilars offer the patient some savings. The example we give is in France. (Humira maker AbbVie) had to drop its price by 80% to meet the biosimilars. In Europe, it's very different.
Humira used to be prescribed more often, peaking at more than 4 million in 2016 and 2019. The number dropped to fewer than 1.5 million by 2022. But the first biosimilar wasn't approved until 2023. What's behind the drug's waning popularity?
There are other competitors that have come out. Humira was first approved for rheumatoid arthritis in 2000 and Crohn's disease in 2007, but up until 2014, essentially the only advanced therapies for Crohn's and colitis were the anti-TNF medicines. Then, Entyvio and Stelara came in. We also have JAK inhibitors you'll see commercials for. Rinvoq is different because it's a pill. There's also Xeljanz. That's for ulcerative colitis. There's another family of pill medicines called S1P modulators, Zeposia and Velsipity. They're not biologics. But you'll actually have a real generic because they're pills. Generics are really felt to be identical or nearly identical, versus a biosimilar. Biosimilars, you can't do an identical biological product.
As an expert on ulcerative colitis and Crohn's, is there anything on the horizon exciting health care professionals?
I don't want to diminish the therapies we have. They're fantastic. I want to emphasize: Despite the commercials that sound scary, the most dangerous medicine we have in treating Crohn's disease, ulcerative colitis, rheumatoid arthritis, and psoriasis is prednisone – steroids. That's been a mainstay of therapy for decades.
Prednisone or related steroids are, by far, the most dangerous, worrisome medicines, even for asthma and other things. Modern medicine is replacing steroids. I'd say the vast majority of your readers will never get anything severe from any of those newer medicines you see the TV commercials for. Don't be fearful.
There are some new approaches. Some of the new approaches are combining medicines I already mentioned. Maybe when you're sick, you need two drugs, and then we'll put you down to one.
There are other advances in looking at other inflammatory markers. Maybe we need to block something else. That's being explored. They also have been looking at stem cell therapies, or other cell therapies, where people have given their T regulatory cells. When your white blood cells, the military, is going out of control, you have the military police, the T regulatory cells. They regulate the immune system to go back to normal. There are a lot of great approaches – very exciting times.
If I may add, we need patients for clinical trials. Every medicine we mentioned, how do they get approved? Because there were volunteers, patients with a disease who agreed. The first part of the trials, often you get the drug or a placebo. You might have a 2-out-of-3 chance, or 3 out of 4, but if you don't get the drug, usually afterwards everyone does.
Of course, some people get better with the placebo. That's the whole point. Clinical trials are free. The testing is free. The medicine is free. Sometimes you get paid. We don't want them to be incentivized to be in the trial, but there may be compensation for your time and the discomfort of getting a colonoscopy.
The medicines that go through clinical trials, if they're working, the manufacturer needs to get prolonged safety data for the FDA. Patients can be on free drugs for years in a clinical trial. Particularly the later trials, you're getting state-of-the-art stuff, and you'll get it free, and you may get it for years.
