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Could Two Targeted Therapies Be Better Than One in Lupus?

<ѻý class="mpt-content-deck">— Mid-stage trial tests a JAK inhibitor as monotherapy and in combination with a BTK blocker
MedpageToday
 A photo of a man’s hand inflamed by systemic lupus erythematosus

In a somewhat daring phase II study, the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) was effective for reducing disease activity in systemic lupus erythematosus (SLE), both when used alone and in combination with elsubrutinib, an investigational inhibitor of Bruton's tyrosine kinase (BTK), researchers said.

But adding the anti-BTK drug didn't improve the efficacy beyond that achieved with upadacitinib monotherapy, according to Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City, and colleagues. As well, the trial initially included an elsubrutinib monotherapy arm, which was terminated halfway through the planned 48-week treatment period after an interim analysis showed no evidence of efficacy.

Results from the were .

Similar findings were for a phase II trial in rheumatoid arthritis (RA) with the same design. If nothing else, Merrill and colleagues observed, the new trial at least shows that upadacitinib -- already approved for RA -- may have a future in SLE. Thus far, no JAK inhibitors have been approved to treat lupus.

A with upadacitinib as a lupus therapy is now underway, expected to finish in October 2026. But the combination with elsubrutinib, designated by developer AbbVie as ABBV-599, now appears to be dead, and the company has announced no plans to develop elsubrutinib as a stand-alone drug, either for rheumatic diseases or hematologic malignancies (the , with AbbVie leading the way).

Why BTK inhibitors for conditions such as RA or lupus? As Merrill's group explained, such drugs are "hypothesized to inhibit B-cell activation and immune complex-driven activation of dendritic cells and neutrophils," which are considered key aspects of autoimmune pathology. This is a different mechanism from JAK inhibitors, which target other aspects of immune dysregulation.

Researchers and clinicians have hesitated, however, to combine different types of targeted immunomodulatory agents for fear of suppressing normal immune function too much.

The new trial offers some reassurance for that concern. For the most part, safety findings in SLEek showed no greater incidence of serious adverse events with the combination product than for upadacitinib alone. Some 12% of patients on the combination developed herpes zoster attacks versus 7% of those on upadacitinib monotherapy and 4% in the placebo group; but otherwise, infection rates were similar between ABBV-599 and the JAK inhibitor alone.

On the other hand, since elsubrutinib provided no efficacy benefit, combining targeted agents that actually work will likely remain off the clinical table.

Study Details

Merrill and colleagues enrolled 341 patients in SLEek, randomized in equal numbers into five arms initially: placebo, upadacitinib at 30 mg/day, elsubrutinib at 60 mg/day, a low-dose combination (15 mg/day upadacitinib plus 60 mg/day elsubrutinib), and a high-dose combination (30 mg/day upadacitinib plus 60 mg/day elsubrutinib). As noted above, the elsubrutinib monotherapy arm was halted early; so was the low-dose combination arm, also on account of poor efficacy. Those patients were still included in the safety analysis but left out of most efficacy results.

Nearly all patients were women (as is typical in SLE) with a mean age of about 43. Roughly 60% were white. Disease duration averaged about 10 years. Some 70% were using corticosteroids, with one-quarter of those patients on doses greater than 10 mg/day in prednisone equivalents. Steroid use was allowed to continue during the trial. About 90% were taking antimalarials at baseline.

The primary efficacy endpoint was achievement of with steroid use at 10 mg/day or less at week 24. This was achieved by 48.5% of the high-dose combination group, 54.8% of patients on upadacitinib monotherapy, and 37.3% of the placebo group.

At week 48, the combination appeared to perform a bit better. SRI-4 rates were 51.5% with the combination versus 45.2% for upadacitinib alone and 32.0% for placebo.

In general, the same patterns were seen for other efficacy measures, including the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) and responder rates. These, too, showed responses for around 40%-50% of patients on the active treatments, whereas placebo responses were in the range of 24%-32% at week 48.

Similarly, overall flare rates were highest with placebo (averaging 2.8 both at 24 and 48 weeks), lowest for ABBV-599 (mean 1.7 and 1.5 at the two intervals, respectively), and with JAK inhibitor monotherapy in the middle (mean 1.9 and 2.0, respectively). Only a few flares were severe and these also were more common with placebo. When overall flares were tracked in a Kaplan-Meier survival curve, no difference was apparent between the two active treatments.

Lab analyses also showed a few hints of possibly superior efficacy for the JAK-BTK inhibitor combination. Numerically greater reductions were seen in anti-double stranded DNA antibodies and interferon gene signatures. Effects on complement levels, on the other hand, were nearly identical.

The study came with some limitations, the authors cautioned, including the relatively small numbers of patients in each arm and the 48-week duration. Also, Merrill and colleagues noted, "[t]he complexity of SLE impedes clarity in accurately scoring and interpreting the equally complicated SLE outcome measures, which sometimes fall short in discriminating between minor and significant disease activity. Additionally, placebo-controlled trials cannot be conducted in the absence of background treatments, which in turn inflate placebo group responses."

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The trial was funded by AbbVie. Merrill reported relationships with AbbVie and numerous other pharmaceutical companies, as did several of her academic co-authors. Eight co-authors were current or former AbbVie employees.

Primary Source

Arthritis & Rheumatology

Merrill JT, et al "Efficacy and safety of upadacitinib or elsubrutinib alone or in combination for systemic lupus erythematosus: a phase 2 randomized controlled trial" Arthritis Rheumatol 2024; DOI: 10.1002/art.42926.