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Medicine Matters rheumatology

The DISCOVER-2 trial was a Phase III trial for guselkumab, which is an anti-interleukin 23 p19 monoclonal antibody, in biologic-naive patients with active psoriatic arthritis. And what is being presented at the ACR is the week-24 data of this trial. This is a new class of medications that is being developed for psoriatic arthritis. Some of the agents in this class have already been approved, of course, for the treatment of psoriasis, where they have been shown to be highly effective. And so now we're proceeding to test them and get them approved for psoriatic arthritis.

DISCOVER-2 was a very large trial, enrolling 741 patients who were biologic-naive who had psoriatic arthritis. DISCOVER-2 accompanies a trial known as DISCOVER-1. DISCOVER-1 was a slightly smaller trial in which patients who were either biologic-naive or TNF-experienced were enrolled. The reason for the larger size of the DISCOVER-2 trial was that the key point was the assessment of structural damage progression as measured by X-ray.

The design was relatively simple. Patients were randomized to either placebo or guselkumab 100 milligrams subQ at weeks zero, four, and then every eight weeks. Or 100 mg subQ at week zero and then every four weeks thereafter. The primary endpoint was at week 24. The patients were very characteristic of a psoriatic arthritis patient group. And the characteristics were a balance between the various arms of the study. About 2/3 of the patients were on background methotrexate.

The primary endpoint of the study was the ACR20 response at week 24. And what was shown was that in the guselkumab Q eight-week dose, 64% of patients achieved ACR20. A similar number in the Q four week arm and then 33% in the placebo arm achieved this ACR20 response. This was a highly statistical separation from placebo. In terms of ACR50 and 70 responses, there were also significant differences puts it from placebo and showing good efficacy at these higher thresholds.

Dactylitis and enthesitis are unique characteristics of psoriatic arthritis, and it is, of course, of great interest for us to see how these clinical domains respond to treatments, since with some treatments such as methotrexate they don't respond very well compared to arthritis or the skin disease. What we saw was that at week 24 complete resolution of dactylitis was achieved by 60%, and nearly 64% achieved this in the Q four week arm compared to 42% in the placebo arm. Again, statistically separated. And in enthesitis, we saw roughly 50% improvement of that kind of clinical domain.

In terms of the skin response, as anticipated, the improvement was very significant, with roughly 80% of patients achieving a PASI75 response, 70% achieving a PASI90, and approximately 45% achieving a PASI100 response. So clearly in this domain interleukin 23 inhibitor is highly effective.

In terms of the modified van der Heijde-Sharp Score, which is a measure of structural damage progression measured by X-ray, it was shown that there was more progression in the placebo group. In the every-four-week arm of the study there was clear statistical separation with very little chart score progression. And in the Q eight-week arm, it was not statistically separated but numerically less than the placebo group, suggesting that this agent clearly has some impact on structural damage progression.

Of course, along with these findings there was also the improvement in outcomes reported by patients such as physical function, quality of life, and so forth. And then in terms of the safety profile of the drug, there was really very little in terms of problem. There were slightly more serious infections in the treatment arm than placebo. There were no deaths.

There was one case of IBD, which is an item of interest with the IL-17 class of agents, but not so much the IL-23 class, and only seven patients with injection site reactions. So by and large, the medicine was shown to be relatively safe and well tolerated.

The reason these findings are important for rheumatologists is that even though we have some highly effective medicines for psoriatic arthritis, including the anti-TNF class and the IL-17 class of agents, as well as IL-12/23 inhibiting medicine, it turns out that oftentimes patients either don't respond to one of these types of treatments, or with time they will lose effectiveness or have safety issues arise.

And so it is very important for us to be able to have medicines that are effective, relatively safe, and are consistent with the biology of the disease in terms of being able to have the ability to achieve low disease activity or remission, which is our goal of treatment. And so having evidence for the IL-23 p19 class of medicine to be able to do this is very important not only for clinicians to be able to choose this type of medication, but also for patients to achieve the goals they seek.

The findings from DISCOVER-2 are very consistent with what was shown in DISCOVER-1 in a larger group of patients and also being able to show the ability to inhibit structural damage progression. But clearly what will happen with these two trials is that there will be an application for approval of guselkumab for the treatment of psoriatic arthritis. And we anticipate that this will follow in due course.

This will give us an opportunity as well to do further research on, for example, persistence of response looking at strategies like treating to target, of potency, of activity, or remission. In some parts of the world there are treatment trials that have to do with reducing medication dosage or withdrawal of medication, so clearly there will be more research with this medication in the future.