A US Food and Drug Administration (FDA) advisory panel yesterday supported Pfizer’s plans for use of tofacitinib (Xeljanz) to treat ulcerative colitis that isn’t controlled by other widely used therapies. The company is seeking to bring this tablet into a field now dominated by injections and infusions.
The FDA didn’t ask its Gastrointestinal Drugs Advisory Committee to weigh in directly on whether the agency should approve a new use of tofacitinib, already cleared for both rheumatoid and psoriatic arthritis. Instead, it asked the advisory panel to vote on three questions related to dosing.
The panel voted 15-0 on two separate questions in favor of Pfizer’s suggested dosing regimen of 10 mg twice a day. FDA staff had raised concerns about the potential for increased adverse effects at the higher dose, with a 5-mg twice-daily dose already approved for use in forms of arthritis.
A selective oral Janus kinase inhibitor, tofacitinib works by interrupting signaling of cytokines in the immune response.
The advisers split 8-7 in the company’s favor on a question about the FDA’s suggestion of a postmarketing trial to compare a 10-mg twice-daily regimen to a 5-mg twice-daily one. They seemed more interested in other approaches for checking on the safety of the drug and in effect rejected the FDA’s proposal in a close vote.
Consultants for Pfizer earlier had argued at the FDA meeting that it would have been difficult to recruit patients for such a study after an approval of a 10-mg twice-daily dose. Bruce Sands, MD, a gastroenterologist at Mount Sinai School of Medicine in New York City, told the FDA panel that there would be ethical questions about enrolling patients in a trial of this kind.
“Patients and physicians alike will look at this approval and look at frankly the data that’s already there from randomized controlled trials and not sign up” for a test of the 5-mg twice-daily dose, Sands told the panel.
According to Pfizer’s background information, 57 (32.4%) of 176 people in the 5-mg twice-daily-dose group were in remission at week 52 in the maintenance study. Of those who got a 10-mg twice-daily dose, 71 (41.0%) of 173 were in remission at that point, while only 18 (10.3%) of the 174 people in the placebo group were.
Mitchell H. Grayson, MD, from Ohio State University School of Medicine, Columbus, echoed the views of many of his fellow panelists in explaining his vote in favor of 10-mg twice-daily dosing for ulcerative colitis. Tofacitinib to date has won FDA approvals at 5 mg twice daily and 11 mg once daily for rheumatoid arthritis. For psoriatic arthritis, FDA has approved 5 mg twice daily immediate release and 11 mg extended release. It remains unclear whether 5 mg twice daily might have worked as well for ulcerative colitis, he said, but he lent his support to Pfizer’s approach.
“There’s enough of a signal there with what I consider a relatively minimal risk in the 16-week period that I think it’s worth it,” Grayson said.
Tracy Matson of Little Rock, Arkansas, the patient representative on the panel, said he also considered the risk-to-reward ratio to be in favor of allowing this option for ulcerative colitis.
“We’re talking about extremely ill patients running out of options,” he said.
More than 900,000 adults in the United States have ulcerative colitis, or a chronic inflammation affecting the colon. They experience recurrent flares of abdominal pain and bloody diarrhea. Many patients end up requiring surgery, Pfizer witnesses told the FDA panel.
Pfizer has proposed an induction course of tofacitinib at 10 mg twice daily for 8 weeks and 5 mg twice daily thereafter for maintenance. A 10-mg twice-daily dose could be continued for 8 weeks, allowing 16 weeks in total, for patients who don’t achieve a good response by week 8, Pfizer said. It’s also proposed allowing a higher maintenance dose treatment option of 10-mg twice-daily continuous dosing for “refractory patients,” defined as those with history of failure of tumor necrosis factor (TNF)–blocking drugs.
Reimbursement Battles Ahead?
The FDA and Pfizer are now working on a new indication for tofacitinib that seems likely to spell out drugs that would have already failed to work for a patient’s ulcerative colitis before the tablet could be tried. These include corticosteroids; azathioprine; 6- mercaptopurine; and TNF drugs, such as infliximab (Remicade, Johnson & Johnson). Lightdale said she could envision having to first put patients on a TNF drug before starting tofacitinib. Lightdale also predicted that she and her colleagues might have to spend time on the phone fighting with insurers to secure coverage of the more convenient tablet for their patients.
“There are a lot of reasons not to set it up this way,” she told the FDA.
The FDA will consider the advice of its panel but is not bound to accept it. The agency’s target date for deciding on the application is in June 2018. In December, Pfizer announced that the FDA had determined that additional review time was necessary because of a submission of new information, which extended the review time by 3 months.
FDA staffers said yesterday that a maintenance therapy benefit had been seen with the 5-mg twice-daily dose as well as the 10-mg twice-daily one. Yet, herpes zoster (shingles) infections stood out as a particular concern for tofacitinib recipients who had already had a poor response to a TNF drug, the FDA said.
Looking at this group, the FDA staff reported what appeared to be a higher number of people taking the 10-mg twice-daily dose who developed herpes zoster. In the maintenance trial 1096, 9 (9.8%) of 92 patients with prior TNF failure who took tofacitinib at 10 mg twice daily developed herpes zoster infections. Of the 83 patients with past TNF setbacks who took the 5-mg twice-daily dose, 2 (2.4%) developed herpes zoster. There were zero cases, though, in the 89 patients in the placebo group in whom treatment with TNF drugs had failed, according to an FDA slide presented yesterday.
“Our aim is to select the lowest effective drug dose and corresponding regimen for patient treatment” because of concerns about potential adverse effects and harm, said Lesley Hanes, MD, MSc, an FDA medical officer, at the meeting.
Several panelists mentioned developments in vaccination against herpes zoster as a likely mitigating factor for this risk with tofacitinib. The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention now recommends recombinant zoster vaccine (Shingrix, GlaxoSmithKline) to prevent shingles in adults aged 50 years and older.
“When we think about these new vaccines, we should be putting this into the mix here,” said panelist Beth L. Jonas, MD, a rheumatologist from the University of North Carolina at Chapel Hill. “This may be a risk that we can manage.”
Sands appeared as a consultant for Pfizer.
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