Convinced largely by encouraging efficacy data, the Food and Drug Administration’s Arthritis Advisory Committee voted overwhelmingly in favor of approval of tofacitinib for the treatment of adult patients with active psoriatic arthritis.
If approved by the FDA, which usually adheres to advisory committee recommendations, the oral inhibitor of Janus-associated kinases (JAK) would be the first JAK inhibitor approved for the treatment of psoriatic arthritis (PsA). Pfizer submitted supplemental new drug applications (sNDAs) for both tofacitinib tablets (Xeljanz) and tofacitinib extended-release tablets (Xeljanz XR) at a dose of 5 mg twice daily and 11 mg once daily, respectively and, despite some reservations with respect to adverse events and lack of evidence regarding inhibition of radiographic progression, the committee voted 10-1 in favor of approval at an Aug. 3 meeting.
All those who voted yes said they felt the applicant had met its burden of proof of efficacy and that the benefits outweighed the risks – such as development of herpes zoster infection – which most members said were in line with risks seen with other biologic agents.“I voted yes and, although there are safety concerns, I feel like it’s nothing different than what we see with other biologics, and I want to make sure that patients have options,” said Jennifer Horonjeff, PhD, a research fellow and patient advocate with the Center for Immune Disease with Onset in Childhood at Columbia University Medical Center, New York, and a consumer representative on the committee.
Dr. Horonjeff added that she hopes there is continued conversation between the sponsor and the FDA on “what we can do to make patients aware of these risks.”
Similarly, committee member Daniel H. Solomon, MD, a professor of medicine at Harvard Medical School and chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, both in Boston, said he sees a “great opportunity for risk mitigation that the sponsor and the [FDA] can take together.”
“We have a clear risk, we have a clear strategy for mitigating the risk, and there are going to be a lot more people exposed to this drug with a known risk, so let’s do something about it,” Dr. Solomon said about a plan put forward by Pfizer, and discussed at some length, to mitigate risks through measures such as vaccination against herpes zoster and additional study.
Temporary voting member Steven Meisel, PharmD, system director of patient safety at Fairview Health Services in Minneapolis added: “These are nasty drugs, but I think those who use them understand that, and this is no different than any of the other nasty drugs in these categories.”
Diane Aronson, a patient representative and temporary voting member on the committee, cast the only vote against approval, citing concerns about the lack of inhibition of radiographic progression of the disease and about the infection risks in a vulnerable population.
Tofacitinib was initially approved in 2012 at a dose of 5 mg, twice daily, for the treatment of adults with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to methotrexate. The extended-release formulation was approved in 2016 at a dose of 11 mg daily.
With respect to the current sNDAs, Pfizer presented data from two placebo-controlled phase 3 trials in patients with psoriatic arthritis. The FDA deemed these trials to be adequate and well-controlled, providing “corroborating evidence of the efficacy of tofacitinib for reducing signs and symptoms of PsA, based on the proportion of patients experiencing the American College of Rheumatology (ACR) 20% response criteria,” according to a report presented to the committee. The report also noted that both phase 3 trials provided evidence of improvement in physical function, but did not provide sufficient evidence that tofacitinib inhibits radiographic progression in PsA.
The report also stated that the safety profile of tofacitinib in PsA was consistent with that established in RA; risks include serious infections, opportunistic infections, malignancy, gastrointestinal perforation, and laboratory abnormalities, including elevations in low-density lipoprotein and triglycerides.
“No new safety signals were identified in PsA,” the report states.
Of note, the sNDAs do not include an indication for generalized psoriasis; an application for that indication was withdrawn in 2016, and Dr. Meisel cautioned against any “unintentional leakage of the use of this drug for generalized psoriasis.”
He and others also cautioned against any implied endorsement in labeling that the drug inhibits radiographic progression of PsA.
Two individuals who participated in the open public hearing portion of the meeting each urged the committee to recommend approval of the sNDAs, with one, Stephen Marmaras, manager of state and national advocacy for the Global Healthy Living Foundation, noting that the joint pain and stiffness associated with PsA are a primary concern of patients.
“Our members with psoriatic arthritis overwhelmingly prioritize joint pain and stiffness as the most bothersome symptoms they experience,” Mr. Marmaras said. “With that in mind, we were encouraged to read that tofacitinib has particularly notable efficacy in treating the joint symptoms of the disease in clinical trials.”
All voting advisory committee members were screened and cleared with respect to potential conflicts of interest.
sworcester@frontlinemedcom.com
