Janus kinase (JAK) inhibitors are a promising next-generation treatment for patients with rheumatoid arthritis (RA). To accompany our Hot Topic Review, medwireNews talks to Professor Roy Fleischmann (University of Texas Southwestern Medical Center, Dallas, USA) about the need for JAK inhibitors and their potential impact on the RA treatment landscape.
Professor Roy Fleischmann (University of Texas Southwestern Medical Center, Dallas, USA)
Fleischmann has been centrally involved in a number of trials of the JAK inhibitor tofacitinib for the treatment of patients with RA, including ORAL Solo, ORAL Standard, and ORAL Strategy.
“I think that [JAK inhibitors] have had an impact” on the treatment of RA, “and I think that they will have an increased impact with time,” he says.
The need for JAK inhibitors
Fleischmann believes that JAK inhibitors meet three important needs: “Not everybody responds to currently available medications – biologic DMARDs [disease-modifying antirheumatic drugs] and conventional synthetic DMARDs – and then there is the convenience issue and some safety reasons why JAK inhibitors may be helpful.”
“We have all sorts of medications for the treatment of RA that are quite effective,” he explains. “Unfortunately, no medication is effective in all patients, and we do have patients who have failed multiple medications including many biologic DMARDs.”
He points out that JAK inhibitors have a different mechanism of action to other RA treatments, and that “they may be effective in patients who do not respond to some of the other molecules.”
Conventional DMARDs – including methotrexate, thalidomide, and sulfasalazine – have pleiotropic mechanisms of action that are not fully understood. “We know that they work in about a third of patients,” says Fleischmann, noting that “we normally start off with a conventional DMARD because of the cost advantage.”
Biologic DMARDs, however, “are all targeted to one mechanism,” he observes. For example, “an anti-TNF [tumor necrosis factor] will absorb or inhibit 99% of the TNF that’s produced in the inflammatory state,” while “an anti-IL [interleukin]-6 will inhibit most of the IL-6, whether it is targeted to the receptor or it is a monoclonal antibody to IL-6 itself,” and “rituximab has one target, the B cell.”
On the other hand, JAK inhibitors result in marked reduction in the production of various pro- and anti-inflammatory cytokines through their effects on the JAK–STAT signaling pathway.
“The difference is the biologics target one cytokine and the JAKs are intracellular and block a particular pathway, but in that particular pathway there are a number of cytokines that are affected,” Fleischmann summarizes.
The other potential advantage of JAK inhibitors is their oral route of administration, believes Fleischmann.
"Not everybody responds to currently available medications – biologic DMARDs and conventional synthetic DMARDs – and then there is the convenience issue and some safety reasons why JAK inhibitors may be helpful."
“The very effective drugs that we have are all injectable or they’re intravenous and that raises problems with respect to administration,” he says.
He observes that the need to travel to a hospital or clinic for intravenous treatments can be expensive and inconvenient for people in many parts of the world. Furthermore, Fleischmann notes that many patients prefer oral medication, particularly in the USA. “Many of my patients in my practice prefer oral medications,” he says.
With subcutaneous treatments, he notes that “there are people who object to needles, there are patients who have injection site reactions to the subcutaneous medication, and there are patients who develop antibodies,” particularly to subcutaneous monoclonal antibody treatments. Having drugs with an oral route of administration and without these drawbacks associated with subcutaneous therapies offers “a significant advantage,” he feels.
In the clinic
“Tofacitinib has been marketed in the US for over 4 years and it is now approved in most countries in the world, while baricitinib is approved in the EU,” says Fleischmann. However, he notes the existence of barriers and patient considerations that determine whether patients actually receive JAK inhibitors in real-world practice.
“Access is the number one [barrier]; patients can’t afford it,” he emphasizes, noting that it receiving a JAK inhibitor “depends where you are in the world and what your access is to the JAK inhibitor, which means cost or insurance coverage.”
There are also some barriers concerning perception of oral medication, he says. In the USA, “it’s a pill” is perceived favorably; “lots of patients take a pill and that can be very effective,” he explains. However, “in some places in the world you take a pill if things aren’t so bad, but you get an injection if things are really bad. So there can be some patient perception about that,” he says.
Fleischmann adds that another important consideration for patients is how long a drug has been available.
“So if I told you that you could use [a drug] which has been around for almost 20 years […] and I know the safety profile and I know the efficacy, or you can use this drug that was just approved 4 years ago […], patients might say ‘I want to use the drug that you have the most experience with’.”
Similarly, “physicians also like to use the drugs that they know really well, and that’s why we use some of the other agents,” says Fleischmann. “We have so many other drugs that physicians are comfortable with that they reserve [tofacitinib]” for patients who have failed other treatment options, he adds.
However, he thinks that “things are changing as we get more experience,” particularly as benefits are being observed in patients who have failed prior treatment with other agents.
“Physicians also like to use the drugs that they know really well, and that’s why we use some of the other agents.”
Beyond treatment barriers, other factors influence whether patients are good candidates for treatment with a JAK inhibitor.
“I think that a patient who cannot tolerate methotrexate or won’t take methotrexate will do well with [JAK inhibitor] monotherapy,” says Fleischmann, and notes that he would think about JAK inhibitor treatment for “patients that won’t take an injectable or infusible medication.”
By contrast, there are certain patient populations that Fleischmann would consider unsuitable for JAK inhibitor therapy at present.
“If a patient is thinking of getting pregnant imminently I don’t think that I would use a JAK inhibitor because there is not very much data on [JAK inhibitor use during pregnancy],” he says. Similarly, he notes a paucity of data on the use of JAK inhibitors by patients with hepatitis B or C virus infection, and says that he would avoid recommending JAK inhibitors for those with a marked decrease in renal function.
Addressing the unanswered questions
Fleischmann observes that the risks associated with JAK inhibitors are reasonably well-characterized. Given the 8-year safety data for tofacitinib and the large phase III trial program for baricitinib, “I think that the risks that we are going to see, we have seen,” he says. “We know that they increase the lipids […], can cause neutropenia and anemia […], and that there is a slightly increased risk of herpes zoster compared with the biologics.” Although opportunistic infections have been reported in the clinical trials of JAK inhibitors, he notes that it is currently not known whether they occurred “just because a patient is in a particular area or taking a certain medication.”
“We know that tofacitinib is comparable to adalimumab but we don’t know if it’s comparable to other TNFs or other biologics with a different mechanism of action.”
Fleischmann also highlights that the safety profile of selective JAK1-targeted agents, including filgotinib and upadacitinib (ABT-494), is less well understood than that of tofacitinib or baricitinib “because we haven’t seen the large phase III trials yet.”
Although “we really do kind of understand the risks” associated with JAK inhibitors, “we don’t really know how to use them quite yet,” concedes Fleischmann. For example, it is not currently known whether a patient with an inadequate response to tofacitinib at a dose of 5 mg would benefit from treatment with the 10 mg dose. “That study hasn’t been done,” he says.
He also notes that “we know that tofacitinib is comparable to adalimumab but we don’t know if it’s comparable to other TNFs or other biologics with a different mechanism of action,” and it is not known whether switching to another JAK inhibitor would be beneficial for patients who have an inadequate response or develop an adverse event during tofacitinib treatment. “We haven’t seen a head-to-head clinical trial of one [JAK inhibitor] versus the other,” he says.
“There are still some unanswered questions,” Fleischmann concludes.
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