Philip Mease, MD, explains the recent Phase 3 data from the DISCOVER-1 and DISCOVER-2 clinical trials which demonstrated guselkumab inhibited radiographic progression, and improved symptoms and pain in patients with active psoriatic arthritis (PsA).
Rheumatology Network interviewed Philip Mease, MD, to discuss recent Phase 3 data from the DISCOVER-1 and DISCOVER-2 clinical trials, presented at the ACR, which demonstrated guselkumab inhibited radiographic progression, and improved symptoms and pain in patients with active psoriatic arthritis (PsA). Mease is Director of Rheumatology Research at the Swedish Medical Center/Providence St. Joseph Health and Clinical Professor at the University of Washington School of Medicine.
Rheumatology Network: Can you tell me a bit about the key findings of the data presented at the ACR Convergence?
Philip Mease, MD: What we did was we presented long-term data for both clinical radiographic and safety outcomes. Safety outcome included both 2-year data for PsA, but also 5-year data for psoriasis. The overall take home message was that benefits that were seen at the primary endpoint of the phase 3 studies at 24 Weeks was sustained over the 2-year period. And in fact, using a strict analysis of the data, including MRI analysis, we saw increasing ACR responses as well as achievement of things like minimal disease, activity threshold, and so forth. So, that was a bit intriguing. Instead of seeing what we often see as a relative plateau, have benefited at the 24-week mark and then kind of a flatline thereafter, we saw climbing results out to week 52 and even beyond. Is it real? Or is it just simply the phenomenon that patients know that they're on something and are sort of more optimistic about their patient-reported aspects of these various measures? Well, that wouldn't be so true about radiographic outcomes, for example, where we saw a sustained benefit for some of the more objective parameters. But the other concept to think about is, are we by inhibiting a molecule that's fairly upstream from interleukin-17 and tumor necrosis factor (TNF)? Are we somehow over time increasing benefit at a biological level? So that's a valuable question. It's a little tough to know the true answer from this data, but it was what we observed. The key points are that the musculoskeletal benefits were maintained, as measured by the ACR20, 50, and 70 responses over time. The enthesitis in dactylitis, complete resolution was sustained and increased over time. These are slightly more difficult-to-treat domains that do actually take a longer time. Another key finding was that there was essentially no progression in the in the overall population in terms of progression of structural damage as measured by X-ray changes. This was most clearly seen in the patients that were responding well. There was an analysis breaking it down by those that were ACR20, 50, 70, or minimal disease activity (MDA) responders or not. And clearly, the patients that were clinically responding had better radiographic outcomes as well. From a safety perspective, we didn't see increasing infections and there was a relatively low serious infection rate. That was pretty consistent over time; it did not increase. We didn't see new issues arising. We didn’t see venous thromboembolism or arterial thromboembolism, which has become kind of a hot topic because of that issue being seen with some other mechanisms or other drug classes. We didn't see any flare or issues with inflammatory bowel disease, ulcerative colitis, or Crohn's disease, and we didn't see a signal related to major adverse cardiovascular events or infection. We didn't see a signal related to herpes zoster. And we didn't see issues related to any abnormal laboratory parameters. So, from a long-term safety and safety monitoring point of view, the longer that we observe the data, 5 years in psoriasis and 2 years now with psoriatic arthritis, it gives us some reassurance that we don't have to, for example, start monitoring laboratory data or turning to the patient and saying there's increasing infection or increasing worries about this or that. It remains a very stable safety pattern over time. All of this is reassuring and allows us to use the drug with fairly good confidence as we're talking to patients about it.
RN: Can you expand upon improvements in physical function joint manifestation and skin clearance?
PM: As I mentioned earlier, what I alluded to is the fact that although there was substantial benefit seen through Week 24, for example, roughly two thirds of the patients had achieved ACR20 response at that point in time. As we track patients over time through Week 100, for example, we saw that result climbing up to nearly 75% of patients achieving ACR20 response, we saw over 50% of patients achieving ACR50, and about a third of patients achieving ACR70 response. So, all of these are climbing or increasing responses over time. We also saw that complete skin clearance was achieved by nearly two thirds of patients, enthesitis clearance was achieved by nearly 70% of patients, and dactylitis by roughly 80% of patients. So complete clearance of skin enthesitis and dactylitis. These are very high rates and, as I mentioned earlier, an intriguing finding to see it increasing over time.
RN: You mentioned the safety and efficacy of this drug. Were you surprised by the results of this study?
PM: Not so much surprised as reassured when we looked at the overall rates of adverse effects at Week 24 and Week 52. As I mentioned earlier, we just haven't seen any meaning signals for malignancy, which is of course a potential concern for patients, or unusual events like herpes zoster or venous thromboembolic events, which I've seen been seen with some other classes of medication. The rates of serious infection have remained low. And so, what we have seen over time was that we didn't see increases of any of these adverse effects. That implies that the drug is not having a meaningful impairment to our immune responses to, for example, infection, and are not finding any organ system problems like liver or kidney effects or cardiovascular effects. This remains very reassuring data.
RN: What do these results mean for both physicians as well as patients with psoriatic arthritis?
PM: it's very important for physicians to have additional weapons in the armamentarium to treat the disease because what we find is that with most medications, biologics or oral synthetic medications, is that patients tend to have a wearing away of effectiveness over time, for a variety of reasons. Either they develop side effects from medications, or they develop drug antibodies against the medicine they're using, or the immune system just simply works its way around the treatment that is being used. So, it's important to have additional effective medications that are that are part of our therapeutic choices. This is very much that type of medication. It's effective. It appears in the various clinical domains of psoriatic arthritis and has, as we've been discussing today, sustained benefits. It can be both highly efficacious and durable. That's important for patients because they're seeking to get to a state of remission or low disease activity where they're not having to think about the disease as much in their life. The drug is given infrequently, just once every 2 months, so they don't have to be constantly reminded about the fact that they're on a medication by taking a daily oral medication or a weekly or every other week injection. And to clinicians, I think it's good for them to be able to offer a patient something that can be effective as well as relatively safe.
RN: Does your team plan on doing any further research on this topic?
PM: Yes. It's not just my team, but it's the global group of rheumatologists that will be enjoined by Janssen to participate in a number of different upcoming trials. For example, there is an upcoming trial studying patients who investigators consider to have what is called axial psoriatic arthritis, so they have psoriatic arthritis, but they also prominently have as part of their disease, spine inflammation and pain. And the entry criteria will include patients who have demonstrable or objective inflammation, as evidenced by MRI scans of sacroiliac joints or the spine. And we'll have a more deep and granular look to see about the effectiveness of guselkumab in this particular population in this particular domain. Another trial that will be underway is a large trial in which the every 4-week and the every 8-week dosing will be tested to look at radiographic outcomes and we’ll have sought more deep, enriched data on the ability of the drug to inhibit structural damage progression as well as show long term efficacy and safety. So those are examples of Janssen’s commitment to continuing to understand better the overall effectiveness and safety profile in patients with various aspects of psoriatic arthritis.