Dennis McGonagle, PhD: The Future of Guselkumab for Psoriatic Arthritis

Dennis McGonagle, PhD

Guselkumab might soon join the small list of IL-23 blockers approved for the treatment of active psoriatic arthritis.

In data planned for presentation during the European Congress of Rheumatology (EULAR) 2020 meeting, a team, led by Dennis McGonagle, PhD, FRCPI, Leeds Biomed Res Ctr, University of Leeds, tested the treatment for patients with key clinical manifestations, including dactylitis and enthesitis, that are difficult to treat and could portend more significant disease burden.

McGonagle explained in an interview with HCPLive® the promising guselkumab results and what the future holds for IL-23 blockers in general.

HCPLive: On the study presented at EULAR.

McGonagle: I'm talking about the use of a IL-23 blocker called guselkumab for the treatment of psoriatic arthritis in 2 large phase 3 clinical trials. The efficacy appears to be comparable to other agents licensed for psoriatic arthritis including the anti-TNFs, the IL-17s, and JAK inhibitors.

These large phase 3 programs also look at other manifestations of psoriatic arthritis including dactylitis or enthesitis.

So, this particular study here that we looked at and presented the EULAR, we combined the data sets from Janssen’s 2 clinical trial programs. And we merged them from the 2 phase 3 studies and we did a specific sub analysis of that on dactylitis or enthesitis.

And what our analysis showed was that there was very good dactylitis resolution over 6 months and the resolution of dactylitis is correlated with the improvement in the polyarthritis and also in resolution of skin psoriasis.

The IL-23 blockers are already have licenses for the use in psoriasis, where they lead to spectacular improvements in skin disease, which is superior to the anti TNF class of drugs.

The resolution of dactylitis was very common in this analysis, and then correlated with the resolution of skin and other parameters.

We also looked up the same evaluation with respect to enthesitis.

HCPLive: Why is enthesitis so difficult to measure?

McGonagle: So, when you make your dactylitis there’s a visible “sausage” digit. When you make your polysynovitis, you see the joint swelling, but enthesitis are a vascular structures that are anchored to the bone and they have lots of cartilage and thick and dense tendon which doesn't readily allow swelling to occur.

You don't usually have the luxury of swelling. So, you're relying only on tenderness and people can have tenderness for other reasons, including mechanical tendinopathy, osteoarthritis, fibromyalgia or chronic pain. So, it is a more subjective measurement.

HCPLive: What are some of the other uses for guselkumab?

McGonagle: The study drug, guselkumab, has been used extensively for psoriasis, where it has a license. Other companies who manufacture IL-23 blockers have advanced trials in inflammatory bowel disease where they there is evidence for efficacy.

HCPLive: Are there any patients with specific comorbidities that guselkumab would not be a safe option for?

McGonagle: Comorbidities are an intrinsic feature of psoriatic arthritis and a third of patients are obese. Hypertension is common, non-alcoholic fatty liver disease is very common.

So, these metabolic issues certainly play into consideration when we use drugs like methotrexate, which can be linked to the fibrosis and could exacerbate non-alcoholic fatty liver disease. So, there is no concerns around the use of IL-23 blockers at this point for comorbidities of disease, and there's a very low risk of serious infection.

HCPLive: What is the next step for your research group in the Discover trials?

McGonagle: There has been no safety signals or serious infections. There's no risk of tuberculosis or neutralizing antibodies. So, the safety profile has been good.

The company will be delighted and I have collaborations with Janssen. The company has given me research grants to look up the use of these drugs in the real world.

We’re interested in better understanding the role of IL-23 in disease pathophysiology.

The reality is this these trials have shown that blocking IL-23 is effective in psoriatic arthritis, but we don't know why.

And the other big research question is the sequence of using biological therapy? As things stand, particularly in Europe, biosimilar anti-TNF is a fraction of the cost of IL-23 blockers.

HCPLive: There’s been some hope that IL-6 blockers could be effective against COVID-19. Could IL-23 blockers also be potential treatments against the virus?

McGonagle: The IL-6 blockers are currently being used in trials for COVID-19 pneumonia. In humans with cytokine storms from other conditions such as adult onset stills disease, IL-6 blockers are effective.

So, the jury is still out on this but it's slightly tangential to this particular disease. There hasn’t been a great deal of talk about IL-23 blockers for COVID-19.

In theory there may be a role for the IL-23 blocker, ustekinumab which also blocks IL-12. And by doing that you block gamma interferon and by doing that you may block IL-6 production by mononuclear cells and macrophages, but hasn't really had traction.

So, the IL- 23 pathway seems to be important, indirectly in immunity via the IL-17 pathway to fungal infections in humans and there's no evidence for IL- 23 having a significant role in viral infections.