JAK Inhibitor Succeeds in Giant Cell Arteritis Trial

WASHINGTON — Giant cell arteritis (GCA) can be successfully treated with the oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq), allowing corticosteroids to be withdrawn, results of a phase III trial indicated.

Among 209 GCA patients receiving the drug at 15 mg/day, 46.4% achieved clinical remission without needing rescue steroids during weeks 12-52 in the study, compared with 29.0% of 112 patients assigned to a placebo group with an extended steroid tapering schedule, according to Peter Merkel, MD, MPH, of the University of Pennsylvania in Philadelphia.

Speaking here at the American College of Rheumatology’s annual meeting, Merkel added that 15/mg/day of upadacitinib hit almost all the secondary efficacy endpoints specified in the trial, with no suggestions of unexpected safety problems.

“Overall, [the drug] provided a favorable benefit-risk profile and represents a potential new targeted therapy for patients with GCA,” he told attendees at the meeting’s first plenary session.

If approved — and manufacturer AbbVie, which sponsored the new study, applied in July for the GCA indication — upadacitinib would become an oral alternative to tocilizumab (Actemra), the only other targeted therapy available on-label for the disease. Merkel noted that steroids remain the “mainstay” of GCA treatment, but the pileup of adverse effects from these agents over time makes them useful mainly for initial therapy and as rescue treatments when flares occur. Having a safer targeted therapy for long-term treatment is thus imperative.

With upadacitinib, AbbVie is following the now well-worn path for JAK inhibitors: testing them for rheumatologic conditions in which biologic drugs have already been approved. GCA would become the company’s ninth conquest for upadacitinib, having won approvals in rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, spondyloarthropathies, and others.

The new multinational study, called SELECT-GCA, commenced in early 2019 and was completed successfully in the face of the COVID-19 pandemic. Merkel and colleagues enrolled 428 patients across 24 countries, randomizing them in a 2:1:1 ratio to the following regimens: upadacitinib at 15 mg/day or 7.5 mg/day, or placebo, all given for 52 weeks. Steroids were tapered to zero over 26 weeks in the two active drug arms, while tapering stretched to the full 52 weeks in the placebo group.

Merkel said the patient sample generally matched the usual profile: just short of three-quarters were women and the mean age was 71. Most patients were newly diagnosed, with a median disease duration of just 41 days, although one participant had lived with GCA for nearly 15 years. Mean steroid dose at baseline was about 35 mg/day in prednisone equivalents.

Eligibility criteria included having received steroid doses of at least 40 mg/day at some point prior to enrollment and age of at least 50. Patients having previously received a JAK inhibitor, or who had tried tocilizumab without adequate response, were excluded, as were those who had taken steroids for extended periods.

The trial’s primary endpoint was “sustained remission,” defined as absence of GCA symptoms from weeks 12-52 and adherence to the tapering schedule. Secondarily, the researchers also set a stricter “complete remission” standard, comprising the above plus normalization of erythrocyte sedimentation rate and C-reactive protein levels.

In general, the 7.5-mg/day dose of upadacitinib was substantially less effective than 15 mg/day, showing some numerical advantages over placebo that mostly did not reach statistical significance. The higher dose, on the other hand, was clearly superior to placebo for nearly all endpoints.

For example, “complete remission” as defined in the protocol was achieved by 37.1% of the 15-mg/day group, 26.2% of those on 7.5 mg/day, and 16.1% of the placebo group. P values for the two active drug groups versus placebo were <0.0001 with the high dose and 0.0699 with the low dose.

Ten other secondary endpoints were also set; Merkel explained that these were evaluated in sequence to avoid reporting “significant” differences that were actually just random chance from the multiple tests. Each one had to be found significant with respect to placebo before the next one would be examined. These endpoints included cumulative steroid exposure, time to first disease flare, numbers of flares, patient-reported evaluations of overall health status and quality of life, and steroid-related side effects.

Because low-dose upadacitinib wasn’t significantly better than placebo for reaching “complete remission,” no further examination of secondary endpoints was conducted. Upadacitinib, however, was superior to placebo for nine of the 11 total such outcomes: only patient global satisfaction failed to show an advantage for the drug, and the last endpoint (steroid side effects) was not reported.

Merkel highlighted the results for disease flares in his talk, which also pointed to the limits of upadacitinib’s effectiveness. Some 34% of patients on 15 mg/day had at least one flare, as did 41% of those on the lower dose, compared with 56% of the placebo group.

On the plus side, it appeared that most patients in all three groups accepted the steroid taper relatively well. As expected from the longer tapering in the placebo group, their cumulative dose was 2,882 mg, versus 1,905 and 1,615 for the low- and high-dose drug groups, respectively. Merkel said these figures indicate that relatively few patients needed significant dose increases to cope with flares.

Safety findings were unremarkable, with no statistically significant differences among groups in rates for any class of adverse event, although Merkel noted that a 52-week study is too short to judge fully. Infections are generally a key risk for any immunomodulatory drug, but serious infections were actually more common numerically in the placebo group. Opportunistic infections and herpes zoster cases were marginally more frequent with upadacitinib.

Only a few cases of malignancies or cardiovascular events were seen. Perhaps the most notable difference between groups was for anemia, in which the event rate was 8.4 per 100 patient-years for the higher upadacitinib group, compared with 3.4 and 3.2 in the low-dose and placebo group, respectively. But again, this was not statistically significant.

Following Merkel’s presentation, two audience members questioned the steroid tapering schedule — one suggesting it could have been longer, the other that it was too long. Merkel replied that the optimal schedule remains controversial: “If you put two rheumatologists in a room… they’ll argue, and if there’s three they’ll fight,” he joked. He said the protocol struck a good balance in reflecting routine practice.

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