Upadacitinib promising in first 52 weeks of SELECT-GCA trial

The JAK inhibitor upadacitinib brought sustained remission in the first 52 weeks of the phase III SELECT-GCA study of patients with new-onset or relapsing giant cell arteritis (GCA).

Forty-six percent of patients treated with upadacitinib 15 mg were in sustained remission – defined as the absence of GCA signs or symptoms and adherence to a steroid-tapering regimen – at 52 weeks compared with 29 percent of those on a placebo (p=0.0019).

Additionally, nine of 11 multiplicity-controlled secondary endpoints were favourable to upadacitinib 15 mg than placebo. No new safety concerns were identified.

“The trial is the first to investigate a JAK inhibitor for GCA … we’re seeking to address a real unmet need here,” said study investigator Dr Daniel Blockmans from the University Hospitals Leuven in Leuven, Belgium, who reported the 52-week results at EULAR 2024. The trial consists of two 52-week periods; the second part is expected to conclude in March 2025. “But we’re already seeing positive results at the first 52 weeks.”

Unmet need in GCA

GCA is the most common systemic vasculitis, causing granulomatous inflammation of medium‐ to- large-sized vessels. Glucocorticoids are the mainstay of treatment to prevent disease flares, but with long-term use comes adverse effects.  The biologic tocilizumab offers an escape therapy during steroid taper.

“Still, patients do not always get better. GCA can also relapse,” said Blockmans. “There are reports of smouldering vasculitis, and this can lead to dilatation of the aorta. I have the impression these medications only suppress the disease.”

Potential new option

Upadacitinib works by inhibiting two JAK-dependent cytokines, interleukin 6 and interferon-gamma (IFNγ); the latter is a seminal cytokine in the GCA pathogenesis.

Of the 428 patients in SELECT-GCA, 210 were randomly assigned to upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. “The inclusion of the lower upadacitinib dose was a regulatory requirement,” explained Blockmans.

The upadacitinib groups received 6 months of steroids as background therapy. The placebo group received a 1-year taper of steroids, which is the standard care for GCA.

Sustained complete remission, defined as sustained remission plus an erythrocyte sedimentation rate (ESR) of ≤30 mm/hr and reduction of high-sensitivity C-reactive protein (CRP) to <1 mg/dL, occurred in 37 percent and 16 percent of patients on upadacitinib 15 mg and placebo, respectively (p<0.0001).

Additionally, a significantly lower proportion of patients treated with upadacitinib 15 mg than placebo experienced at least one disease flare (34 percent vs 56 percent; p=0.0014).

Significant changes in SF-36* and FACIT-Fatigue** from baseline to week 52 were seen for upadacitinib 15 mg. However, changes in the TSQM*** at 52 weeks and glucocorticoid-related adverse events showed no clear benefit for upadacitinib.

As for upadacitinib 7.5 mg, it fared better than placebo across most endpoints but did not reach statistical significance.  There was no increased risk of major adverse cardiovascular events (MACE) or venous thromboembolism with both upadacitinib doses and placebo in this GCA population, considering they have a higher risk for these events compared with the rheumatoid arthritis (RA) population.

“It was effective and safe in older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study [which showed higher MACE events than a TNF inhibitor in RA patients]. We didn’t see any of those problems in this GCA population.”

No imaging was done in the SELECT-GCA trial, which Blockmans said should be considered in future studies.