Dr Joan Merrill: Insights on Anifrolumab

Joan T. Merrill, MD, is the director of clinical projects in the arthritis & clinical immunology research program at the Oklahoma Medical Research Foundation in Oklahoma City, OK. Her major interests are clinical trial design and pharmacodynamics in the study of lupus treatments. Dr Merrill met with The Dermatologist to discuss her insight into anifrolumab and its benefits in treating moderate to severe systemic lupus erythematosus (SLE).

What kind of effect on skin rash have you seen in patients treated with anifrolumab based on the latest data¹?
The most recent posthoc analysis from the two TULIP phase 3 trials is really interesting because it specifically looks at anifrolumab’s ability to improve upon skin rash and arthritis in patients with lupus instead of looking at all the organs lumped together. This is especially relevant for dermatologists because skin is one of the most impacted organs in SLE.

In these trials, investigators evaluated just the skin rash component in patients using different disease measures that have different approaches to evaluating this common manifestation of SLE, including SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group index (BILAG), and modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI).

The important takeaway from this new analysis is that anifrolumab showed a consistent improvement in proportions of skin disease responders vs placebo using each of these measures: 13.5% using SLEDAI, 15.5% using BILAG, and 15.6% using mCLASI.

Finding the same endpoint using measures that are less and more sensitive to change shows that we can detect differences in both major and more subtle changes in skin activity that might otherwise have been missed. The new data from these two trials increases our confidence in what we continue to learn about anifrolumab’s potential to show improvements in SLE that might matter to patients.

What concerns might dermatologists have regarding adverse effects to anifrolumab, such as upper respiratory tract infection, bronchitis, infusion-related reactions and herpes zoster?
Upper respiratory tract infections and herpes zoster are all expected risks with a drug that interferes with your IFN-1 signaling, because IFN-1 plays a major role in the body’s immediate defense against viruses and some bacteria. This is especially true of reactivation of herpes zoster (shingles). We expected to find some increase in these adverse effects. The surprise was that they weren’t all that common or severe. Most of these events were manageable and mild to moderate.

How does anifrolumab compare to other current treatments for SLE?
The patient populations with SLE that have been tested with anifrolumab and other treatments have ranged in severity from moderate to severe manifestations, so it's a wide range of patients. Of course you cannot compare two treatments properly without a head to head study, but given some similarity in trial designs, anifrolumab is looking very promising.

When you have a patient who is coming in with SLE—which is a person either on the verge of hospitalization or who is hospitalized—there may be some organ-threatening or life-threatening disease. It’s hard to say how any biologic is going to perform in this situation because most biologics are still too new and the data isn’t there. Generally speaking, I would say that, in the short run, when a patient comes in with life-threatening disease, they are going to be treated aggressively with high-dose steroids. The new biologics and/or other strong immunosuppressants will come in fairly early for those patients to try to keep things under control.

For moderate disease, we think long term. In many cases, we think we could go with a biologic and then have time for it to kick in. We do not have to necessarily do major immune suppression until it kicks in.

Regarding how anifrolumab compares to other treatments, we don't know yet. We also do not know much about how it would perform on its own without background treatments. Remember, most of these studies were add-ons. One of the strengths of the anifrolumab phase 2 and 3 studies is that because the patients were being treated fairly aggressively in the placebo group, showing improvement is an achievement because we were already giving good care, and now we're doing even better.

Is there anything else notable about severe SLE or anifrolumab that you would like to share?
The surprise, for me, was how well tolerated anifrolumab. We also have so much to learn about all these immune signals, including what would be the optimal dosing.

Patients would like a treatment that will help their rash but not cause shingles. Right now, when we develop drugs for almost any disease, we tend to go with a dose where the majority of the people are responding, without too many developing side effects. Our patients are heterogenous enough that it would be better medicine if we could grade enough biomarkers to gauge optimized individualized dosing more than we do today.

In the future, that's the research I would like to see done. There is no doubt at all that the 300-mg dose of anifrolumab has proven to be quite effective, but I wonder what we could do if we could have a more sophisticated approach to be able to optimize the dose in every person.

When it comes to SLE, what is your favorite pearl?
One of the most important things for us to remember is that when you see lupus skin disease all by itself, it does not appear to be a different disease than when it is seen along with other forms of lupus in separate organs. It seems as if we still have not figured out why sometimes lupus goes to this organ or that organ, but it may target specific organs because of variables within those organs that enable autoimmune reactivity. We have seen every different combination of organs involved, and the underlying pathology does not sort itself out by the organ involved. Although it is a bit heterogenous from patient to patient, SLE has certain themes that are common, and you cannot say that the underlying cause of skin disease is across the board different than the underlying cause of arthritis or other aspects of the disease.

Reference
1. Merrill JT, et al. Anifrolumab effects on rash and arthritis in patients with SLE and impact of interferon signal in pooled data from phase 3 trials. Oral presentation at: the 2021 European Alliance of Associations for Rheumatology (EULAR) European Congress of Rheumatology; June 3, 2021; virtual. Abstract ID: 1471.