medwireNews: At the end of 2017, the indication for ixekizumab was expanded to include psoriatic arthritis (PsA). Previously approved for plaque psoriasis, the interleukin (IL)-17A inhibitor may now be given to adult patients with active PsA in the USA, while the EMA has approved its use in adult patients with PsA and an inadequate response or intolerance to one or more DMARDs. Ixekizumab can be used alone or in combination with methotrexate.
The approval of ixekizumab for the treatment of PsA was based on the results of two phase 3 randomized controlled trials, SPIRIT-P1 and SPIRIT-P2. Here, we summarize the key data from these trials, and discuss the place of ixekizumab in the PsA treatment landscape with SPIRIT-P1 lead investigator Philip Mease, from Swedish Medical Center and the University of Washington in Seattle, USA, and PsA specialist Laura Coates, NIHR Clinician Scientist at the University of Oxford in the UK.
The value of ixekizumab in the PsA treatment landscape
It increases choice
So where does ixekizumab fit into the current PsA treatment landscape? Philip Mease believes that it is “a very appropriate targeted treatment for psoriasis and PsA.” He adds that the IL-17 pathway is “very important” in the pathogenesis of these diseases, and that the SPIRIT-P1 and SPIRIT-P2 trials provide “proof of the pudding that by inhibiting IL-17 we have strong efficacy across many clinical domains including skin, nails, arthritis, enthesitis, and dactylitis, as well as the ability to inhibit structural damage progression.”
Mease stresses the importance of having a choice of multiple agents with different mechanisms of action for the treatment of PsA, given that many drugs either have no benefit in certain patients, or have initial benefit followed by a loss of response.
“In clinical practice we are often evaluating patients for sustained efficacy, and when sustained efficacy is no longer present, and we're losing efficacy, then we need to change horses and get on a fresh horse that is going to be potentially effective,” he says.
It provides an alternative IL-17 inhibitor
In addition to having various drugs available that target different pathways, Mease also believes that “it's good to have more than one drug in a given pathway because sometimes the patient may have side effects or poor tolerability or lack of efficacy with one drug in that pathway but still have benefit from a different drug in that pathway.” Ixekizumab targets the same signaling pathway as secukinumab, another IL-17A inhibitor that is approved for the treatment of PsA in the USA and in Europe, as well as other agents under development for PsA including bimekizumab and brodalumab.
[Ixekizumab] gives us another really solid option
Laura Coates explains that ixekizumab and secukinumab are very similar drugs, “although there are key differences in the way that they are made, in the way the molecule is actually put together.” She adds that the IL-17 receptor antibody brodalumab “blocks more broadly” than ixekizumab and secukinumab because other cytokines also act through the IL-17 receptor, while bimekizumab targets both IL-17A and IL-17F.
“So they're all slightly different,” she summarizes, noting that ixekizumab “gives us another really solid option” for the treatment of PsA.
Which patients should be considered for ixekizumab treatment?
Patients with skin involvement
“I think it's important to think about all the different domains of disease whenever we're picking a treatment,” says Coates, noting that “we tend to focus mostly on joints as rheumatologists.”
“I think we're pretty good at picking up dactylitis; maybe sometimes we're less good at looking for enthesitis and axial disease, and then obviously we need to consider the skin.”
She emphasizes that ixekizumab is “very good for skin disease,” and is therefore “a really good option for patients where skin is a big problem to them.” Indeed, results of the UNCOVER-1, -2, and -3 trials demonstrated that ixekizumab is superior to placebo and etanercept in terms of improvement in physician's global assessment of psoriasis and the proportion of patients with at least a 75% improvement in in Psoriasis Area and Severity Index score.
Mease adds that, for example, “if a patient is particularly bothered by psoriasis, if they have quite a bit of body surface area involved with psoriasis, if they have very troublesome scalp psoriasis,” or have problems with itching or genital psoriasis, then they may stand to benefit from ixekizumab treatment.
Any patient with PsA has the capability of responding to ixekizumab
Patients with MS or tuberculosis
Coates also notes that ixekizumab and other agents targeting the IL-17 pathway seem to have a favorable safety profile in patients with multiple sclerosis (MS) and latent tuberculosis, which is important because TNF inhibitors have been associated with exacerbation or reactivation of these conditions, meaning that patients with PsA and MS or tuberculosis can be difficult to treat.
Patient preference and access issues
Another factor to take into account when deciding whether to prescribe ixekizumab is the route of administration. Mease points out that a number of oral agents, including conventional DMARDs such as methotrexate and the targeted agents apremilast and tofacitinib, are available for the treatment of PsA, and “some patients will strongly prefer an oral medication over an injectable medication” such as ixekizumab.
He adds that access to drugs is another key deciding factor, “at least in the United States, where insurance companies may have a preference list for which medicines you try first.”
Cautions and monitoring requirements
Patients with inflammatory bowel disease
While he believes that “any patient with PsA has the capability of responding to ixekizumab,” Mease cautions that the drug should not be taken by patients with very active inflammatory bowel disease. Indeed, because clinical trials in patients with plaque psoriasis demonstrated that Crohn’s disease and ulcerative colitis, including exacerbations, occurred more frequently among participants treated with ixekizumab versus placebo, the US and European labels both urge caution when prescribing the drug for patients with inflammatory bowel disease, and recommend that such patients should be monitored closely. The ixekizumab labels also carry precautions for hypersensitivity and infection risk, and state that the drug cannot be given to patients with active tuberculosis.
Live virus vaccines
Moreover, it is recommended that ixekizumab should not be given together with live virus vaccines, because no data are available on the response to these vaccines in PsA patients undergoing ixekizumab treatment.
In the past, this “would apply to the [live virus] vaccination against herpes zoster, the zoster vaccine,” says Mease, but “nowadays there is a non-live virus vaccine called Shringrix for zoster, so that's less of an issue.” However, he points out that other live virus vaccines, such as the 17D yellow fever vaccine, should be avoided.
How ixekizumab compares with other drugs for the treatment of PsA
Comparison with other IL-17 inhibitors
“The efficacy and safety [profile] of ixekizumab appears to be very similar to that of secukinumab” on the basis of currently available data, observes Mease. He notes that the two agents elicit a similar response in patients with peripheral arthritis: both are able to inhibit radiographic progression, and similarly low rates of infection have been observed.
At the moment there are certainly not enough data to compare the different [IL-17 inhibitors] and say how well they perform against each other
Coates agrees that the IL-17 inhibitors appear to be similar, and “as a class they have certain features.” However, she stresses that there are no head-to-head studies between them; therefore, “at the moment there are certainly not enough data to compare the different [IL-17 inhibitors] and say how well they perform against each other.”
Comparison with other biologics
While the currently available data suggest that ixekizumab and other IL-17 inhibitors may have some similarities, Mease says that “there are differences with the TNF inhibitors, phosphodiesterase inhibitors, the newly emerged JAK inhibitors, and abatacept.” For example, ixekizumab has demonstrated a stronger effect in clearing the skin than other treatments, he says, and Coates notes that, in general, “it works pretty quickly, so people will feel better quicker.” Mease observes that IL-17 inhibitors and TNF inhibitors appear to be similar in their efficacy for peripheral arthritis, enthesitis, and dactylitis.
Turning to safety, Mease says that the safety profile of ixekizumab is “overall relatively good,” noting that infection rates with IL-17 inhibitors, which are low overall, are “probably a bit lower than for the TNF inhibitors.” He explains that people treated with ixekizumab “may develop oral thrush or vaginal candida,” because “IL-17 is a cytokine which is specifically responsible for helping defend the body against candida infection, and when you inhibit it then it opens up the body a little bit more to candida.” However, he says that candida infections in these patients are “usually mild-to-moderate and pretty easily treated, and oftentimes we just continue on with treatment with the IL-17 inhibitor without needing to interrupt treatment.”
Furthermore, if a patient was switching from a TNF inhibitor to an IL-17 inhibitor, Mease feels he could reassure them that they would not be moving to a medicine with a worse safety profile.
“The overall area under the curve of safety issues with IL-17 inhibitors appears to me to be slightly better than the TNF inhibitors,” he says. However, like Coates, he emphasizes that in the absence of any head-to-head data, firm conclusions cannot be drawn.
Future research goals
Ongoing clinical trials will help to address the current lack of head-to-head comparisons between IL-17 inhibitors and other biologic agents. Mease says that one trial between ixekizumab and adalimumab (NCT03151551) and one between secukinumab and adalimumab (NCT02745080), are “going on as we speak,” so “we will have a better idea of comparative efficacy and safety between those two classes of medications” when these trials have been completed. Both trials are currently recruiting, and are expected to be completed in 2019–2020.
We don't as yet have any biomarkers, for example from blood samples, that could teach us if a patient is going to respond better to an IL-17 inhibitor than a TNF inhibitor, or a JAK inhibitor
Another current knowledge gap concerns the use of ixekizumab in patients with very early PsA, a population where “typically we see better responses,” notes Mease.
“The trials that we have are in patients who have either previously been treated with a DMARD such as methotrexate (SPIRIT-P1), or in patients who have been previously exposed to TNF inhibitors (SPIRIT-P2), so we don't have data on what would happen if this were used in a patient group where it was the first ever agent used,” he explains. While acknowledging that health insurance companies are unlikely to allow the use of ixekizumab in the first-line setting, he thinks that “having information about its efficacy in very early patients” would be useful.
Moreover, Mease indicates that “we don't as yet have any biomarkers, for example from blood samples, that could teach us if a patient is going to respond better to an IL-17 inhibitor than a TNF inhibitor, or a JAK inhibitor,” which is another potential avenue for future research.
Mease feels “pretty reassured and pretty confident” that new serious safety issues not seen to date are unlikely to occur with longer-term exposure to ixekizumab, but cautions that “we don't have really long-term data.”
And Coates agrees, adding that “whenever you have a new drug you want long-term extension data and safety data, and real-world data.”
She describes the results of a recent study showing that that only around a fifth of patients started on biologic therapy would have met the criteria for inclusion in clinical trials, which include “very selected patients.” Therefore, “you’re treating very different patients” in everyday clinical practice, and “real-world data will be really helpful going forward I think,” she says.
Coates also points out that “there have been some concerns about injection site reactions from the trial dataset,” and that “knowing how much of a problem that is for patients, and whether it leads to discontinuation in real patients in routine clinic, would be useful.”
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