An emerging class of medications called janus kinase inhibitors (JAK inhibitors, or jakinibs) is offering new hope to patients with rheumatoid arthritis (RA) who don’t find relief with other treatments.
What are Jakinibs?
Jakinibs are a new class of medication, sometimes called oral biologics. The word “biologic” is misleading, however, because jakinibs work in an entirely different way than the biologics that have been used to date. Jakinibs are small molecules that work inside cells. Traditional biologics such as etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia) and Infliximab (Remicade) block pro-inflammatory cytokines from outside.
Jakinibs are taken by mouth. Traditional biologics are given through infusions or injections.
How do Jakinibs Work?
Jakinibs block the enzymes JAK1, JAK2, JAK3, and tyrosine kinase 2, which play a role in the cell-signaling process that leads to the inflammatory and immune responses seen in RA and other conditions. Jakinibs interrupt the signaling pathway.
“They are like the first translator. They are the molecules that take that signal from the cell surface and start moving it down the chain of command,” explains Donald Miller, Pharm.D, professor and chair of the pharmacy practice department at North Dakota State University in Fargo, N.D.
Are Jakinibs FDA Approved for Rheumatoid Arthritis?
Yes. The U.S. Food and Drug Administration (FDA) approved Xeljanz (tofacitinib) in November 2012 for adults with moderate to severe active RA who do not respond to or who cannot tolerate methotrexate. The 5-mg tablet is taken by mouth twice a day, alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
Tofacitinib was tested at two doses – 5 mg and 10 mg – but the FDA only approved the lower dose. Herbert Baraf, MD, a clinical professor of medicine at George Washington University School of Medicine in Washington, D.C., who participated in Phase III clinical trials of tofacitinib, says that’s a downside because the 10-mg dose had more significant positive x-ray data, in his opinion.
“Can you escalate the drug or cut the dose back if you need to and do you have another option to move on to? The answer with this drug is no because we have one only dose level,” says Dr. Baraf, who hasn’t yet prescribed the medication.
Are Jakinibs for My RA?
If your RA symptoms are well-controlled with methotrexate or biologics, a jakinib likely isn’t right for you. However, jakinibs could provide a great new treatment option if you have moderate to severe active RA and an inadequate response or intolerance to methotrexate.
Yet, it is unclear how these drugs specifically help improve symptoms. “My suspicion is that JAK inhibitors block multiple cytokines,” explains John O’Shea, MD, scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases who has worked with Pfizer on the development and research of jakinibs. “There are more than 200 cytokines and about 60 of them use the JAK pathway. In all the autoimmune diseases we have, we don’t know exactly which cytokine is the trouble maker.”
In general, jakinibs may not be used as a first-line therapy for RA, partly because methotrexate and biologics work well for most patients and there is more data on those medications.
“We’ve had ten years of practitioners using [biologic] drugs to have a good understanding of their efficacy and safety. Clinicians have only had a year of using JAK inhibitors, so there are still questions about it,” explains Dr. O’Shea, who discovered a JAK pathway and holds a patent with the National Institutes of Health for targeting JAKs.
What Will Jakinibs Cost?
Initially some wondered if jakinibs would be cheaper than biologics, since producing a small molecule drug is not considered as complicated. But Miller says that hasn’t been the case. “Tofacitinib is $2,000 a month before insurance, so there wasn’t a big advantage there,” he explains.
And that’s another reason why Dr. Baraf hasn’t yet prescribed it: “I just don’t see $2,000 a month being justifiable for a pill that is not being dosed at the more effective dose level”
How much your insurance will cover depends on your insurance carrier. One study conducted by an industry affiliated group and presented at the ACR 2013 annual meeting reported that, from the provider or insurance company perspective, anti-tumor necrosis factor (anti-TNF) drugs were likely to work better, more often than a jakinib. If so, using jakinibs might be reasonable when more standard therapies have failed.
What Are The Potential Side Effects of Jakinibs?
The FDA warns that jakinibs may cause an increased risk of serious infections, tuberculosis, cancers and lymphoma as well as high cholesterol, respiratory tract infections, headache and diarrhea in some patients.
Researchers presenting at ACR 2013 said that malignancies in patients on tofacitinib occurred at a similar rate as what’s expected for patients with moderately to severely active RA on traditional biologics or DMARDs.
What’s Next for Jakinibs?
A spokesperson for the FDA says the agency can’t disclose information about drug applications under review. Dr. O’Shea, who published an article in the January 10, 2013 issue of The New England Journal of Medicine about jakinibs, says there are about 17 new ones in clinical trials as of November 2013, approximately nine of which are aimed at treating autoimmune diseases such as RA.
Jakinibs being studied for RA include:
Could Jakinibs Help Kids With Arthritis?
Daniel J. Lovell, MD, associate director of the division of rheumatology at Cincinnati Children’s Hospital Medical Center and chair of the Pediatric Rheumatology Collaborative Study Group says research is in the works to see if children with arthritis would be helped by these drugs.
“It’s risky to assume things will be exactly like they are in adults in terms of effectiveness and side effects,” Dr. Lovell explains. “It may be JAK inhibitors work better in children than adults. If it turns out they are similar, then they will probably be used for children with JIA who don’t respond to other therapy.”
Dr. O’Shea agrees there is still a lot of research to do overall as well. “There will be ongoing trials to determine exactly how we use these drugs for all types of arthritis,” Dr. O’Shea says. “I think the future is exciting.”