Pharmaceutical companies know that no matter how impressive the clinical data or how speedy the regulatory approval, a drug won't deliver health benefits or drive returns if doctors aren't prescribing it.
That hang-up is front and center in the field of rheumatoid arthritis, where an explosion of new therapies over the last two decades has upped competitive pressures and pushed doctors to reconsider treatment options. Next generation members of the Janus kinase, or JAK, inhibitor class could cause further disruption too, threatening blockbuster biologics like AbbVie's Humira (adalimumab) and Amgen's Enbrel (etanercept) that have long held top positions in the RA drug market.
BioPharma Dive talked with a handful of rheumatologists about this dynamic therapeutic space, the problems patients still face even with expanded treatment options, and how the doctors see RA care evolving down the line. They were:
- Ana-Maria Orbai, assistant professor of medicine in the division of rheumatology at Johns Hopkins University School of Medicine
- Angus Worthing, private practice rheumatologist in Washington
- Jas Singh, professor of medicine and epidemiology in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham's School of Medicine
- Uzma Haque, assistant professor of medicine in the division of rheumatology at the Johns Hopkins University School of Medicine
- Aruni Jayatilleke, associate professor in the Division of Rheumatology at Drexel University College of Medicine
These interviews were conducted separately. They have been condensed and edited for clarity.
BIOPHARMA DIVE: How has the treatment landscape for RA changed in recent years?
WORTHING
"What we're seeing is an additional mechanism of action and class of drugs as targeted molecules and small molecules; so far they're JAK inhibitors, but essentially these are as effective and similar to biologic drugs from the past two decades, but taken in pill form. This comes on the heels of about two decades of biologic drug use, which was after maybe 10 years of use with DMARDs [disease-modifying anti-rheumatic drugs] such as methotrexate."
JAYATILLEKE
"The last few years have shown an increase in the number of and the mechanisms of actions of the different drugs that are available for rheumatoid arthritis, which is great for our patients — especially some of those who haven't had a good response to what we used to consider first-line agents.
More and more we are trying to determine what medications patients will respond to prior to prescribing them, rather than following an algorithm. There's this concept of precision medicine and personalized medicine as to what are the patient's factors, what medications might work for them or what might not work for them. If possible, let's try and get those first so that they have the best chance of success."
We've been hearing a lot about JAK inhibitors lately. Why the hype?
ORBAI
"They are new, a different mechanism which acts maybe more closely to where the signal transduction occurs in the immune cells. But also it seems to be more convenient because these are oral molecules as opposed to injectable biologics. That's why it seems to be taking ground — and not only in rheumatoid arthritis, I can tell you."
WORTHING
"By far the most interesting thing about it is that it's a pill. It's obvious, but people prefer to take pills, usually, compared to giving themselves injections or coming in for injections or infusions."
What's the current treatment paradigm for RA?
ORBAI
"Most people, when they just come with new onset arthritis, will get methotrexate if there's no contraindication. Methotrexate is a very old medication that's not very selective, but it's cheap and it was one of the first meds shown to be effective in rheumatoid arthritis. Most insurances will ask that your patients fail this before going to any more specialized and more expensive medication.
"There are many ways for us to attack rheumatoid arthritis."
Ana-Maria Orbai
Johns Hopkins University School of Medicine
There are people who won't be checked on methotrexate, so then you move on to second-line biologics — though we really shouldn't call them second-line. Biologics are right now state-of-the-art in rheumatoid arthritis, and sometimes it doesn't make a lot of sense to have people fail methotrexate, which has toxicity, in order for them to get to these treatments.
If you want to group these, you'll have TNF inhibitors, IL-6 inhibitors, signal inhibitors like abatacept that inhibit talking between the T cells, and then you'll have rituximab, which is a B cell inhibitor. There are many ways for us to attack rheumatoid arthritis."
HAQUE
"Anti-TNF agents still hold the share of the market as far as the first biologic is concerned. Unless the patient has a specific co-morbidity, I will reach towards an anti-TNF agent first. I think that practice is still quite prevalent among rheumatologists.
The other big issue is also insurance companies. In general, for most of our insurance at this point, they usually ask us to fail one or two anti-TNF agents before we can go to another biologic agent. I think that also drives the decision making somewhat.
But if I, let's say, go to Xeljanz, or tofacitinib, as the first-line agent, I can tell you that I would likely have a huge pushback from the insurance companies."
What feedback are you getting from patients? Are most happy with their current therapy? Any aspects of their disease they wish was being better managed?
WORTHING
"Everybody has similar goals in that they want to feel better, they want to minimize the potential for side effects of the drugs that they're taking.
But then a lot of people will equate administration with toxicity, so if it's a shot or an IV people might think at first that that drug must be more toxic than a drug that's taken as a pill. It takes a little bit of time to inform people that a synthetic DMARD such as methotrexate might have more toxicity for somebody with liver problems, somebody who plans pregnancy, etcetera ... than a biologic drug.
Backing up a little bit, it's very common for people to wonder — once they're doing well after months or years — when they can reduce doses or frequencies of drugs or whether they can stop taking their medications for rheumatoid arthritis. And it's often pretty frustrating for people to learn that we expect rheumatoid arthritis to come back if they stop medicines."
ORBAI
"Patients have a different perspective than doctors in terms what their objectives are for treatment, and there is a lot of effort in rheumatology to try to include that perspective.
One aspect that came from patients was that fatigue, for example, was very important for them. Other things, in terms of their priorities, were pain, stiffness and just in general life impact — it's very important for patients and underestimated by doctors.
It's also due to the nature of our visits, right? We'll count the joint, we look at the laboratory markers, at the typical disease activity index. But patients are also interested in this life-impact aspect. Unfortunately, with how drugs are approved, there's no specific indication for any of these drugs or verbiage allowed by the FDA [that allows physicians to say] that it decreases fatigue, improves quality of life.
These tend to be communicated more softly. They're not in the label, and I know that patients are looking for that."
Does drug pricing or insurance coverage come up in your conversations with patients?
SINGH
"It's a huge issue. And the fact that the prices are going up rather than going down; technology gets cheaper over time, drugs are getting more expensive over time. If this were a cost of living adjustment, I could understand. But it's more than that.
"If the price of gas was going up the way the price of Enbrel has gone up, we'd have people out in the streets demonstrating."
Jas Singh
University of Alabama at Birmingham's School of Medicine
I think patients would benefit and healthcare delivery systems would benefit if there was some oversight. I do understand we have a market economy, but if the price of gas was going up the way the price of Enbrel has gone up we'd have people out in the streets demonstrating."
HAQUE
"It's very occasional that we have to really advocate for a patient where something is not being approved and the patient really needs it. But most of the time, at least in our clinics here at Hopkins, it's not a big concern for the patients directly.
I can tell you that when we sit down and talk about the first biologic — and again, it's most likely an anti-TNF — I do talk about the fact that there are five of them [and ask the patient], 'What would be your preference, in terms of how frequent injections would be versus an infusion?' and then I do tell them that you may have your insurance that prefers one over the other. Sometimes it's an issue, but most of the time, like I said, it's not.
WORTHING
"The price of drugs comes up every single day, either directly because patients report cost being a barrier to treatment or indirectly in that there is often a days-long or weeks-long delay while prior authorization is obtained. I'm in a group of 20 and we have approximately one prior authorization [full-time equivalent] for every two doctors. So to say that's an increase in overhead and a drag on expenses is an understatement."
What's next for RA treatment?
SINGH
"Personalized medicine is something that both patients and physicians want. We don't yet have it, but I think there's a lot of advances occurring on that front. Maybe in five years, maybe in 10 years we're going to have that; maybe sooner than later. I think that's probably the next frontier in treatment of all chronic conditions, not just rheumatoid arthritis.
People working in the arena; I think data are not strong as yet. People are coming up with biomarker series assays, stuff like that. It's kind of exciting, but nothing has yet captured the way HER2 receptors captured breast cancer.
Oncologists have been able to make strides in personalized medicine, and I think they are at the forefront of this. I think rheumatology is going to be the No. 2 specialty getting there, but we need a lot more funding, a lot of work in the area. We're not there as yet, but patients definitely are always interested in that."
The treatment of rheumatoid arthritis, even though we have become very good at it, is still by trial and error."
Uzma Haque
Johns Hopkins School of Medicine
HAQUE
"We really want to be able to understand what is driving rheumatoid arthritis in each unique and specific individual, so that we don't waste as much time with different medications, DMARDs and biologics, not knowing if the patient will show an effective response to those.
As a rheumatologist, what I'm looking forward to is, when I get a patient who is newly diagnosed with rheumatoid arthritis, I get with them a clear guideline of: in this patient, the rheumatoid arthritis is being driven by IL-6, or by TNF, or by some T cells or B cells — so the best medications to initially try would be one, two or three at this point.
The treatment of rheumatoid arthritis, even though we have become very good at it, is still by trial and error."
