Exploring the effects of dapirolizumab pegol on disease activity markers in SLE

The phase 3 PHOENYCS GO trial (NCT04294667) investigated the efficacy and safety of dapirolizumab pegol, a novel CD40 ligand inhibitor, for the treatment of systemic lupus erythematosus (SLE).

In this interview, we spoke with Dr Janet Pope (University of Western Ontario, London, Ontario, Canada) about the rationale, methodology and findings of her analysis of the PHOENYCS GO trial, investigating the effects of dapirolizumab pegol on markers of SLE disease activity, anti-double stranded DNA (anti-dsDNA) antibodies and complement proteins C3 and C4.

Abstract: Dapirolizumab pegol treatment and improvement in laboratory markers of disease activity in patients with systemic lupus erythematosus: 48-week results from a phase 3 trial. EULAR 2026, June 3– 6, London, UK.

Questions

1. What is the mechanism of action of dapirolizumab pegol? (0:21)
2. What do we already know about dapirolizumab pegol from the PHOENYCS GO trial? (1:09)
3. What was the rationale for your analysis evaluating markers of disease activity? (2:03)
4. Could you describe the design and methodology of your analysis? (3:28)
5. What were the key findings, and what are their clinical implications? (4:30)

Transcript

I’m Dr Janet Pope. I’m a rheumatologist and Professor of Medicine at Western University in the other London, so London, Ontario, Canada, and I’ll be presenting on behalf of several authors for the poster.

What is the mechanism of action of dapirolizumab pegol?

Dapirolizumab pegol or DAPI, we sometimes call it for short, is a CD40 ligand inhibitor. What does that mean? Well we know that B cells talk to T cells, and you can interfere with that activation by suppressing CD40. A CD40 ligand inhibitor will therefore downregulate or dampen inflammation through B and T cells.

DAPI is a PEGylated, large macromolecule that is present in the circulation. It could have other theoretical advantages going beyond any kind of labeling right now, for example in women who are pregnant, the drug does not cross the placenta. But that is for another day of discussion.

What do we already know about dapirolizumab pegol from the PHOENYCS GO trial?

The PHOENYCS GO trial was a phase 3, randomized, controlled trial where patients with active SLE on background therapy stable dose, with or without glucocorticoids, were randomized to add either DAPI or placebo in a double-blinded fashion. We found that BICLA, which is a composite endpoint used in lupus trials, was strongly positive and statistically significantly superior to placebo. DAPI was also well tolerated and had improvements in other features of lupus.

What was the rationale for your analysis evaluating markers of disease activity?

The rationale was to determine, given that DAPI had already shown a clinical effect, what was happening with patients with respect to their markers of disease activity. These are not direct markers of disease activity. However, in general, positive anti-dsDNA antibodies and low complement proteins are considered markers of serologically active lupus. The rationale was to see what would happen to anti-dsDNA antibodies and the complement proteins with the active treatment, DAPI, versus placebo.

We want complement proteins C3 and C4 to normalize or to increase closer to normal, and we want anti-dsDNA antibodies to decrease. In both cases, the complements and the anti-dsDNA antibodies, there was a favorable improvement of these markers of inflammation with DAPI versus placebo. It was also significant, and took place quite quickly after the drug was started, so it was a fast and significant improvement in these activity markers of lupus.

Could you describe the design and methodology of your analysis?

This was a secondary analysis and not part of the main study, where presumably drug approval will occur as a result of the main outcome measurement.

This was really a secondary, exploratory analysis. Other lupus studies have also sought to determine if the drug is genuinely having an effect by improving markers of disease activity, such as anti-dsDNA antibodies and complement levels. That’s why this analysis was performed.

We looked at the mean group difference at each time point from baseline throughout the randomized controlled trial – around 48 weeks. This analysis looked at how rapidly things changed and whether placebo was different from DAPI.

What were the key findings, and what are their clinical implications? 

As expected, the placebo group didn’t change much, showing almost a flat line with no improvement. Whereas there was a rapid improvement with DAPI, with anti-dsDNA antibodies normalizing in many more patients or improving in level. A strongly positive anti-dsDNA antibodies result is a bad thing, whereas a weakly positive result is better. Complement levels also moved towards normal.

I think the clinical implications are that a drug showing positive results in patients with non-renal lupus, particularly those with skin involvement, joint involvement, low blood counts, positive serology, and other features of lupus, could, once approved, provide benefit to many patients with lupus. I think having the added data of normalizing anti-dsDNA antibodies and improving the complements in many patients gives some degree of reassurance that the drug is doing what it is supposed to and lowering markers of disease activity in lupus.