In one trial, 59.8 percent of patients on a low dose of tofacitinib monotherapy and 65.7 percent of those receiving a higher dose achieved a 20 percent improvement at 3 months, compared with 26.7 percent of those given placebo, according to Roy Fleischmann, MD, of the Metroplex Clinical Research Center in Dallas, and colleagues.
The second study, in which patients were also taking methotrexate, found 20 percent responses at 6 months in 51.5 percent and 52.6 percent of the low- and high-dose tofacitinib groups, compared with 28.3 percent of those given placebo, according to Ronald F. van Vollenhoven, MD of the Karolinska Institute in Stockholm, and colleagues.
In that trial, there also was a comparator arm in which patients received the tumor necrosis factor inhibitor adalimumab (Humira); 47.2 percent of patients in that group also had 20 percent response.
Both studies were published in the Aug. 9 issue of the New England Journal of Medicine.
"The clear success of JAK inhibition as a treatment for rheumatoid arthritis, if confirmed by robust long-term efficacy assessed with the use of both clinical and radiographic measures, represents an important clinical advance," wrote David A. Fox, MD, of the University of Michigan in Ann Arbor in an accompanying editorial.
Tofacitinib inhibits the JAK/STAT signaling pathway and was shown in phase II studies to be beneficial in patients who had not responded to conventional therapies.
The first of the phase III trials included 610 patients with active disease despite treatment with at least one conventional drug or biologic agent.
They were randomly assigned to receive 5 mg or 10 mg of tofacitinib or placebo twice daily.
More than 85 percent were women, two-thirds were white, and mean age was 51. Disease duration was slightly over 8 years.
The numbers of patients having 50 percent improvement according to the American College of Rheumatology (ACR) criteria in the 5-mg and 10-mg groups at 3 months were 31.1 percent and 36.8 percent, compared with only 12.5 percent for placebo, Fleischmann and colleagues reported.
ACR 70 percent responses were seen in 15.4 percent and 20.3 percent of the 5-mg and 10-mg groups compared with 5.8 percent of the placebo group.
In the trials, tofacitinib treatment was associated with side effects including infections, increases in low-density lipoprotein (LDL) cholesterol, and reduced neutrophil counts.
In the monotherapy trial, seven serious infections occurred, including cellulitis, liver abscess, and pyelonephritis, and 32 serious adverse events overall were seen.
One of these was fatal congestive heart failure in a woman with previous cardiovascular disease.
By month 3, LDL cholesterol increased in 13.6 percent of the 5-mg group and in 19.1 percent of the 10-mg group.
While neutrophil counts fell with tofacitinib treatment, none of the patients with moderate-to-severe neutropenia developed serious infections.
In the combination therapy trial, serious infections were seen in 3.4 percent and 4 percent of the 5-mg and 10-mg groups and in 1.5 percent of the adalimumab group.
Two patients in the 10-mg group developed tuberculosis, and two deaths occurred, one in a patient receiving adalimumab and the other in a patient receiving 5 mg of tofacitinib.
Small changes in serum creatinine were seen in all treatment groups.
In his editorial, Fox emphasized that close scrutiny of the safety profile of tofacitinib will be needed, including vigilance for other potential adverse developments such as autoimmune syndromes.
"A better understanding of the safety profile of tofacitinib will influence the consideration of when in the course of rheumatoid arthritis clinicians should consider this novel approach," Fox wrote.
Source: Oral JAK Drug Succeeds in RA
Copyright © www.orthopaedics.win Bone Health All Rights Reserved
