How lupus clinical trials are evolving

In the past half-century, scores of investigational drugs for lupus have seemingly failed in clinical trials. GSK’s Benlysta (belimumab) is unique in winning approval from the FDA and European regulatory authorities.

Anifrolumab from AstraZeneca, which would be a first-in-class type I interferon inhibitor, is one of the most promising investigational drugs for treating systemic lupus erythematosus (SLE). SLE is the most common form of lupus. The PDUFA date for anifrolumab is September 30, 2021, according to the Antibody Society.

A fully human monoclonal antibody, anifrolumab binds to subunit 1 of the type I interferon receptor, potentially calming the impact of pro-inflammatory cytokines involved in lupus.

Anifrolumab has shown promise in SLE patients in the pivotal TULIP Phase 3 program.

[Related: AstraZeneca’s TULIP trials highlight role of interferon in lupus]

Getting to this point, however, hasn’t been easy, as lupus symptoms vary considerably. It’s telling that lupus is sometimes called “the disease with a thousand faces.”

To learn more about lupus clinical trials, we sat down with Dr. Joan Merrill, director of clinical projects, arthritis and clinical immunology program at the Oklahoma Medical Research Foundation, who was involved in the anifrolumab TULIP studies.

What have been some of the most significant traditional challenges for lupus clinical trials?

Merrill: There have been a couple of things that got in the way of lupus trials. One is just the heterogeneity of the disease itself. It’s going to be impossible to find one treatment for everybody. And once you find a treatment for most people, you’re also going to have a lot of work to do over the next 20 or 30 years to figure out how to optimize it for each person because it’s just not going to play out identically.

For many years, we worked on the assumption that we had to have quite a lot of aggressive background medication in lupus patients. And as a result, we had new treatments play out against a heterogeneous population on heterogeneous drugs — just increasing the degree of complexity of what we were looking at and rendering trials almost uninterpretable.

One innovation in the AstraZeneca program, and some others, is tapering of background steroids in patients.

They paid a lot of attention to that. If a patient was getting better, you taper down steroids. It’s actually standard of care because steroids have a lot of toxicities themselves. Tapering steroids enabled the efficacy signal to shine through for [anifrolumab] and for some drugs developed around the same time.

We have had dozens of drugs that seemed theoretically promising end up failing in lupus. It’s been a very heart-wrenching experience over the last decades for this disease. It is a very underserved disease. It affects minority populations the most and is challenging to treat.

We’re making progress now. I think the main message from this particular situation is that this progress is hard-won, hard-fought and is a long time coming.

Can you talk more about the impact of background medicines in lupus patients and how that impacts lupus clinical trials in general?

Merrill: We are learning to taper background medicines to try to unload the noise we have in these patients. Remember, if you’re on medication x, and then you add an investigational drug, you have the risk that the medication will interfere with it or be redundant to it.

Traditionally, we have very high placebo response rates in lupus patients with really quite painful illness and disfiguring rashes. Those were not placebo effects. They were the result of so much background treatment going on and endpoints being iffy.

So the first goal is to try to unload some of the background noise from the medication. The second goal is improving the quality of data.

I want to underscore that this [TULIP] program somehow managed to achieve both [goals] a little bit earlier than some of the other trials that are coming along now.

There’s a third piece to this: we need to enter patients into these trials who are sick enough. Many trials now have adjudication of entries where you have a blinded person who’s an expert in lupus answers questions like: ‘Am I convinced of the diagnosis of lupus?’ ‘Is the disease activity appropriate for putting a person in a placebo-controlled trial?’

Remember, this goes two ways. You don’t want patients who are too sick because they might get a placebo. But if you have patients that are too well for a study, you have the issue of — if it ain’t broke, and you can’t fix it.

Addressing those three components will make a big impact, and I think the TULIP trials are an example of the beginning of that impact.

How did you get interested in studying lupus?

Merrill: In medical school, I was convinced that I wanted to be a neurologist, and I saw a sign on the wall that asked, ‘Do you know enough about the immune system? Come to the NIH for a month in your fourth year, and you will learn more than you ever imagined.’

So I called the phone number. They immediately hired me, and it was all about lupus, and the rest was history. So, I got kidnapped by immunologists.

At the Oklahoma Medical Research Foundation. I was fortunate to join a group led by Dr. Judith James, who wanted to have a laboratory for real precision medicine in lupus. And we’ve had a series of small projects and true drug developers working with us. Sometimes we are working by ourselves, where we’re drilling down on the immunology of what happens when you take drugs off, put drugs on. And we’re looking not just at new drugs and development, but some of the standard of care drugs that we’re using now, which we’re using in a very 18th century way. We run it up the flagpole and see if anyone salutes, and that’s you know that’s so non-21st century. We can be doing so much better.