Jonathan Kay, MD; Ronald F. van Vollenhoven, MD, PhD

Disclosures

December 07, 2015

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Jonathan Kay, MD: Hello and welcome. I am Dr Jonathan Kay, professor of medicine and director of clinical research in the division of rheumatology at University of Massachusetts Medical School and UMass Memorial Medical Center, both in Worcester. I am reporting here in San Francisco from the 2015 American College of Rheumatology (ACR) Annual Scientific Meeting and am here today with Dr Ronald van Vollenhoven, professor of clinical therapy research and chief of the Clinical Trials Unit in rheumatology at the Karolinska Institutet in Stockholm, Sweden. Professor van Vollenhoven is about to move to Amsterdam, where he will be professor of rheumatology at both of the institutions in that city and a welcome addition to the Dutch rheumatology community.

Today we are going to talk about some of the abstracts and papers that have been presented at the ACR meeting about therapy of inflammatory arthritis. Ron, there were some interesting papers presented predominately about small molecules and some of the biologic agents with different mechanisms other than tumor necrosis factor (TNF) inhibition. Baricitinib and, to some extent, filgotinib were presented at this meeting, and so were sarilumab and interleukin (IL)-17 inhibition. There is a really interesting abstract[1] that Peter Taylor presented at the Late Breakers session that discussed a trial comparing the efficacy of baricitinib, adalimumab, and placebo. What was your impression of this?

Ronald F. van Vollenhoven, MD, PhD: Well Jon, this is one of the really big stories here at the ACR Congress—the new molecular pathways that are being targeted as Janus kinase (JAK) inhibitors. Of course there is already a JAK inhibitor available in the United States and many other countries, but not yet in Europe. There have been a number of presentations and discussions here about other JAK inhibitors and especially with baricitinib, which is going through a very large phase 3 program, including several different very large trials, some of which have already been published and some of which were presented here at the meeting.

Indeed, there was one here that was just presented by Professor Peter Taylor[1] from the United Kingdom that compared baricitinib with placebo, which is what you always get in phase 3. We already know that baricitinib is better than placebo, so the trial is almost unnecessary, but this trial also had patients on adalimumab, the anti-TNF agent that is used very widely, and it was the first head-to-head trial making that comparison between baricitinib and an anti-TNF.

Dr Kay: Now that's a gutsy move because this was not just adalimumab 40 mg subcutaneously every other week as monotherapy, such as in the test trial compared with tocilizumab, but this set up to be a real comparison between the effective, approved dose of adalimumab with methotrexate against this novel JAK1/2 inhibitor with methotrexate pill therapy.

Dr van Vollenhoven: It was gutsy to try to say: "We are going to go ahead against an anti-TNF, which we know is a very good treatment." There was a little bit of precedent because with tofacitinib—the one that is already approved—there was a trial[2] that had the comparison. It was not designed to make the comparison statistically, but it provided the background; and that's, I think, why they dared to do it.

Dr Kay: Right.

Dr van Vollenhoven: In this trial, baricitinib did indeed show that it achieved better clinical responses than adalimumab. Of course, adalimumab also has very good clinical responses, and both were much, much better than placebo. But baricitinib did win out on the clinical efficacy outcomes—ACR20, ACR50, ACR70, etc. Across the board, the clinical outcomes were statistically significantly better for baricitinib.

More on Baricitinib

Dr Kay: There were other, secondary outcomes—not just efficacy outcomes but radiographic outcomes, patient-reported outcomes. What were your thoughts about those?

Dr van Vollenhoven: I think that you have to have the balanced view because there was not much radiologic progression at all in these patients, which is what we are seeing in most clinical trials now. But there was a little bit more radiologic progression in the baricitinib group than there was in the adalimumab group, and then of course more again in the placebo group. So the differences were very small, but there was some statistical significance achieved. The clinical benefit for baricitinib did not completely translate into a radiologic benefit, and there was some discussion of whether it had to do with patients who did not achieve the low C-reactive protein.

So it is a balanced picture. You can also say: "Well, how about the other side of the coin?", which is the safety of the drug. And then, of course, we also have known now for a decade and a half since anti-TNFs were introduced that they are, generally speaking, very safe with some specific warnings or concerns. And with baricitinib, this is also true, but the warnings and concerns are a little bit different. With baricitinib, you see a little bit more of the cytopenias, which is something that you probably would have to monitor as a practitioner—liver function and enzyme elevations. Then there is a question of infections, which actually look pretty good, but there is always a slightly increased risk for infections with all of the biologics, with all of the new treatments, which is logical because they are immunosuppressants.

Dr Kay: The baricitinib development program is fairly robust and relatively complete, so it looks as if this agent is probably going to go before the US Food and Drug Administration (FDA) in the relatively near future. Where might this be placed in the therapeutic armamentarium as there is already a JAK3 inhibitor on the market?

Dr van Vollenhoven: That is a difficult question to answer because the issue is: If you have good drugs from which to choose, what is your most important priority? Is it efficacy, or is it safety? Is it your own experience as a doctor with the drug, or is it that maybe there is a patient convenience aspect with tablets as opposed to injections? Weighing all of these factors in an appropriate way will present a real challenge for the profession, and we need input from patients. We may have to do it at an individualized level, and we probably will need more data also from phase 4 from the postmarketing analysis.

Dr Kay: In the United States, price plays a major part in the therapeutic decision. Do you confront the same situation in Europe?

Dr van Vollenhoven: Yes, price is actually just as big or even a bigger issue in Europe than in the United States. I think that over the next few years, pricing considerations for therapeutics and therapeutic strategies will drive the big decisions. That is the sad but true reality. Prices have been very high for new therapies, and there is a reason for that, but at the same time it's not sustainable. Now we are seeing prices moving to slightly better levels that make it sustainable, and so hopefully all patients who need these treatments will be able to get them.

Dr Kay: Now there were two other significant abstracts presented at oral sessions about baricitinib.[3,4]

Dr van Vollenhoven: Yes, again it is a very big program. I mean there is a whole set of phase 3 trials, and all of them have shown very good efficacy and a very acceptable safety profile that gives a good benefit-to-risk ratio.

More New Agents

Dr Kay: Now filgotinib is another JAK1/2 inhibitor that is a little bit earlier on in development than baricitinib as it is in phase 2 rather than phase 3. Several abstracts were presented here showing efficacy and safety of that compound.[5,6]

Dr van Vollenhoven: That's right. Filgotinib has been developed by the Belgian company Galapagos NV together with AbbVie Worldwide, and it was shown in phase 2 to also have efficacy and reasonably good safety. There is a little bit of a difference in the specifics of the JAK inhibition—baricitinib is 1/2 and tofacitinib is 1/3 but mostly 3 maybe. Filgotinib was supposed to be mostly just 1. There was always the question of whether it makes a big difference, but I can assure viewers that it doesn't make that big a difference; clinically, it seems that they are all pretty much equivalent.

Dr Kay: Let's turn now to different mechanisms of action. Sarilumab is a monoclonal antibody against the IL-6 receptor. It is available and has been studied in two different doses: 150 mg and 200 mg. Patients take it subcutaneously every other week. There were presentations here about that drug compared with placebo.

Dr van Vollenhoven: I think you have to say that an anti-IL-6 is expected to behave like the one that has already been available for many years, tocilizumab, and that is exactly what happened with sarilumab. It had very good efficacy, rapid onset of action, good effects in patients who have not responded to methotrexate but also in patients who did not respond to anti-TNF therapy. It does have the same risk profile as tocilizumab, with anti-IL-6. For instance, some patients do develop cytopenia, and some patients will have liver function elevations. The cholesterol levels do increase, and there is also this peculiar finding that maybe there is a downregulation of these acute phase reactants or that maybe it's been harder to use those in clinical practice.

Dr Kay: At this meeting, the ACR recognized Professor Pierre Miossec of Lyon with the Distinguished Basic Investigator Award, a very well deserved award for his seminal work discovering IL-17, which, from observations, now plays a major role with therapies in spondyloarthritis, psoriatic arthritis, and psoriasis. There were some presentations about IL-17 inhibition in psoriatic arthritis and spondyloarthritis.[7,8] What are your thoughts there?

Dr van Vollenhoven: That is an exciting story in rheumatology. I think that's the story for 2015, not just for this Congress, that there is now a new pathway that we are targeting with anti IL-17. And there are two drugs, as you know. Secukinumab has already been approved for psoriasis and is getting very good results in clinical trials in psoriatic arthritis, spondyloarthropathies including ankylosing spondylitis, and the other elements of that. The results with IL-17 blockade are very, very exciting. It's going to give us a new tool in our toolkit for treating these patients with seronegative diseases.

Dr Kay: That is very exciting. Our toolbox has to get bigger as the therapeutic armamentarium expands. Ron, it's always a pleasure speaking with you and hearing your perspectives on new therapies and what is going on at the meeting. It is a great pleasure to see you here in San Francisco, and I look forward to seeing you again next year in Washington. Thanks very much.

Dr van Vollenhoven: Thank you.

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