Numerically more biologic-naive patients responded to the JAK inhibitor
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Oral tofacitinib (Xeljanz) was an effective treatment for rheumatoid arthritis (RA) in patients who had previously received biologic therapies and also in those who were biologic-naive, although numerically more biologic-naive patients responded in the drug's clinical trials, researchers said.
Pooled data from nine trials showed that, at 3 months, scores on the Clinical Disease Activity Index (CDAI) among biologic-naive patients were below 10, indicating low disease activity, in 14.3% (95% CI 11.5 to 17.4) of patients on placebo compared with 32.4% (95% CI 29.5 to 35.4) of those receiving 5 mg tofacitinib twice daily and 39.8% (95% CI 36.8 to 42.9) of those on 10 mg twice daily (P<0.0001 versus placebo), according to Christina Charles-Schoeman, MD, of the University of California Los Angeles, and colleagues.
And among those who had previously had an incomplete response to biologic treatment, low disease activity was achieved by 14.4% (95% CI 9.4 to 20.6), 29.5% (95% CI 23.8 to 35.8), and 35.9% (95% CI 29.7 to 42.5) of the placebo, 5 mg, and 10 mg dose groups, respectively. While the two active treatment groups had greater responses than placebo (P<0.001 and P<0.0001), the 95% confidence intervals overlapped, the researchers reported online in Annals of the Rheumatic Diseases.
Data have been lacking on comparative efficacy of biological therapies for RA among patients who have not yet received any of these agents and those who have previously had an inadequate response to agents such as tumor necrosis factor (TNF) inhibitors, meaning they stopped the treatment because of a lack of efficacy or because of adverse events.
"It is important that new RA therapies demonstrate efficacy and tolerability in RA patient populations with varying disease duration and prior treatment exposure to reflect the variability seen in clinical practice," wrote Charles-Schoeman and colleagues.
Tofacitinib differs from most of the newer RA treatments in that it is a small molecule JAK inhibitor rather than a biologic. To see how its efficacy and safety compare among biologic-naive and inadequate responders, the researchers analyzed data from four phase II and fivephase III studies that evaluated the drug as monotherapy or in combination with conventional disease-modifying anti-rheumatic drugs such as methotrexate.
In these studies, 1,071 biologic-naive patients received 5 mg tofacitinib twice daily, while 1,090 received 10 mg twice daily, and 651 were given placebo.
In the biologics inadequate responder group, the corresponding numbers were 259, 253, and 193, respectively.
Baseline demographics across the treatment groups were generally comparable, according to the authors.
In analyses that simply compared the efficacy of tofacitinib versus placebo, regardless of previous biologic exposure, outcomes favored the active treatment.
Compared with placebo, significantly more patients receiving the 5 mg dose of tofacitinib achieved 50% and 70% responses according to the criteria of the American College of Rheumatology (ACR50 and ACR70). Among the biologic-naive, 32.7% had ACR50 responses and 12.9% had ACR70 responses, while among inadequate responders the numbers were 24.4% and 9.7%, respectively.
Similarly, improvements in Disease Activity Score in 28 joints (DAS28) and on the Health Assessment Questionnaire Disability Index were greater among the patients receiving 5 mg of tofacitinib twice daily compared with placebo (P<0.05).
However, when comparing the efficacy according to previous biologic status, only numerical differences were found. For instance, DAS28 responses of 3.2 or lower (low disease activity) were achieved at 6 months by 16.3% (95% CI 13.9 to 19) of patients receiving 5 mg in the biologic-naive group and by 18.3% (95% CI 13.5 to 24) of inadequate responders.
For those given 10 mg twice daily, that degree of DAS28 response was seen among 23.3% (95% CI 20.5 to 26.2) of biologic-naive patients and by 23.0% (95% CI 17.6 to 29.1) of the biologic inadequate responders.
As in most of the efficacy endpoints, there were overlapping 95% CIs.
A few exceptions to the numerical superiority for biologic-naive patients were seen, such as in ACR20 responses at 3 months for both the 5 and 10-mg groups.
Another exception was the subgroup of patients who had been treated with two or more TNF blockers before receiving tofacitinib. Those patients "generally had poorer efficacy responses than biologic-naive patients and those with one previous TNF inhibitor exposure."
For adverse events, the incidence rates were numerically higher for patients receiving the active treatment compared with placebo.
Discontinuations because of adverse events were seen in 10.1%, 9.1%, and 9.6% of the placebo, 5 mg, and 10 mg groups who were biologic-naive, and for the inadequate responders, in 18.9%, 14.8%, and 15%, respectively.
Serious cases of herpes zoster were seen in none of the placebo patients in either biologic-naive or inadequate responder groups, and in 0.3% of both doses in the biologic-naive group as well as in 0.6% of the 5 mg tofacitinib group but in none of the 10 mg patients.
However, patients who were on concomitant glucocorticoids had higher rates of serious adverse events, herpes zoster, and serious infections, which is consistent with previous reports.
"In summary, tofacitinib was effective in reducing the signs and symptoms of RA when used before or after [biologic therapies]. With a few exceptions, tofacitinib treatment resulted in greater efficacy in biologic-naive versus biologic inadequate responder patients."
And because the safety was similar across subgroups, "these results suggest that tofacitinib provides an effective treatment option for both biologic-naive and biologic inadequate responder patients," the researchers concluded.
A limitation of the study was the pooled analysis of studies with different designs and patient populations.
The study was sponsored by Pfizer. Some co-authors are employees of Pfizer.
Charles-Schoeman and co-authors disclosed relevant relationships with Pfizer.
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