PHILADELPHIA—In kidney transplant recipients, the Janus kinase (JAK) inhibitor tofacitinib better preserved renal function while maintaining similar efficacy compared with cyclosporine, but the investigational immunosuppressant did lead to more adverse events. These were the findings of Phase 2b study presented here at the American Transplant Congress (ATC), the joint annual meeting of the American Society of Transplant Surgeons and the American Society of Transplantation (Abstract #4).
Tofacitinib is being developed as a primary immunosuppressant that could replace calcineurin inhibitors (CNIs). While calcineurin inhibitors have significantly extended short-term renal graft survival by lowering rates of acute rejection, long-term transplant survival rates remain disappointing, largely because of the nephrotoxicity of the agents.
Compared with the CNI cyclosporine, a tofacitinib-based immunosuppressive regimen led to higher measured glomerular filtration rate (GFR) at 12 months, but rates of serious infections, including cytomegalovirus (CMV) disease and posttransplant lymphoproliferative disorder (PTLD), also were higher.
“There are some very attractive components of the new drug in terms of improvement of GFR, but the concerning part was the development of PTLD in some patients, which appears to be dose related or exposure related,” said Ginny L. Bumgardner, MD, PhD, who co-moderated the session during which the results were presented. Dr. Bumgardner is Professor of Surgery in the Division of Transplant Surgery and Associate Dean for Research Education at the Ohio State University Medical Center.
“It really will be refining the use to target a dose that is efficacious for prevention of rejection and for the maintenance or improvement of GFR and renal function without incurring the side effect of the infections with CMV as well as the PTLD,” she said in an interview at the meeting. “And it seems like it's achievable.”
Study sponsor Pfizer is considering what's next for the agent in this indication.
“Pfizer is evaluating the efficacy and safety data from the recently completed and ongoing extension studies to determine the appropriate next steps for the transplant program,” spokeswoman Victoria Davis wrote in an e-mail interview.
Filings for the agent in rheumatoid arthritis are anticipated in the United States and European Union by the end of 2011, and Pfizer is also studying oral tofacitinib in psoriasis and inflammatory bowel disease, and topical tofacitinib in psoriasis and dry eye disease, Ms. Davis added.
Two Co-Primary Endpoints
Included in this randomized, multicenter, partially blinded, parallel-group study were 322 patients randomized to the cyclosporine group (109 patients) or to one of two tofacitinib groups—a more-intense regimen (106 patients) or a less-intense regimen (107 patients), noted Flavio Vincenti, MD, of the Division of Nephrology at the University of California, San Francisco, during his presentation of the findings.
Patients in both tofacitinib groups were started on a 15-mg twice-daily dose of the agent. Those in the more-intense group were switched to a 10-mg twice-daily dosing schedule after six months, while those in the less-intense group made that transition after three months.
In terms of treatment discontinuation, 43.4% to 44.9% of tofacitinib patients had discontinued therapy by the end of 12 months, compared with 28% in the cyclosporine group, Dr. Vincenti said. All patients received basiliximab induction, mycophenolate mofetil, and prednisone.
“The patient population was immunologically low-to-moderate-risk patients receiving kidneys from deceased donors or mismatched-HLA living donors,” he added.
The two co-primary endpoints were incidence of biopsy-proven acute rejection (BPAR) at six months and iohexol-measured glomerular filtration rate (GFR) at 12 months.
The rates of BPAR at six months were 17.7% in the cyclosporine group, 16.1% in the more-intense tofacitinib group, and 12.4% in the less-intense tofacitinib group, the study abstract noted.
“The rates were low in the three groups, and tofacitinib easily met the non-inferiority criteria compared with cyclosporine,” Dr. Vincenti said.
In terms of the secondary efficacy endpoint, very few patients had a rejection of Grade IIB or III, and no patients receiving tofacitinib had antibody-mediated rejection, he added.
In African-American patients, however, the rejection rate was higher in the tofacitinib groups than in the cyclosporine group—about 30% versus about 10%, he noted.
“I think you have to remember that the number of patients is small,” Dr. Vincenti said during the question-and-answer session following his presentation.
“We have to look more carefully at the pharmacodynamics/pharmacokinetics, see exactly what's going on with that. I think it's going to be an area of interest to find out whether this was just an abnormal cluster or in fact it's going to be a reproducible finding that requires additional investigation.”
In terms of renal function, mean measured GFR at 12 months was 53.9 mL/min in the cyclosporine group, 64.6 mL/min in the more-intense tofacitinib group, and 64.7 mL/min in the less-intense tofacitinib group, the study abstract noted.
“At 12 months, the difference was about 10 mL/min,” Dr. Vincenti said. “This is not only statistically significant but also clinically significant.”
There was a lower incidence of chronic allograft nephropathy in protocol biopsy with tofacitinib—25.0% in the more-intense group and 23.9% in the less-intense group, compared with 48.3% in the cyclosporine group—as well as a lower rate of new-onset diabetes after transplantation—9.9% in the more-intense group and 9.3% in the less-intense group, compared with 20.8% in the cyclosporine group—the abstract reported.
Higher Rates of Serious Infection
On the other hand, adverse events were more common with the investigational agent than with cyclosporine. For example, rates of serious infection were 44.5% and 37.0% in the more-intense and less-intense tofacitinib groups, respectively, versus 25.3% in the cyclosporine group.
Incidence of CMV disease was higher with tofacitinib—19.5% in the more-intense group and 13.3% in the less-intense group, compared with 4.5% in the cyclosporine group—as was the incidence of BK virus nephritis—2.6% in the more-intense group and 3.9% in the less-intense group, compared with 1.1% in the cyclosporine group.
During the first year, there were two cases of posttransplant lymphoproliferative disorder in the more-intense tofacitinib group, one case in the less-intense tofacitinib group, and zero cases in the cyclosporine group. Of the five patients with PTLD, four had central nervous system involvement. Two additional cases of PTLD occurred after the first year in the more-intense tofacitinib group.
“Tofacitinib exposure measured by time-weighted concentration at two hours post-dose was associated with the risk of developing PTLD,” Dr. Vincenti said. “In fact, all five patients who developed PTLD had tofacitinib exposure above the median level in the first six months posttransplant.”
During the question-and-answer period, Michael Abecassis, MD, MBA, of North-western University, who co–moderated the session with Dr. Bumgardner, asked Dr. Vincenti to speculate on the next step for the agent.
Dr. Vincenti responded, “I think you have two products that are in Phase 2/Phase 3 that eliminate CNI. One of course is belatacept that is awaiting, hopefully, FDA [Food and Drug Administration] approval, and the second one is the JAK3 inhibitor.
“I think we're entering an era where we can eliminate CNI effectively—maybe not all patients at the present time—and I think from this data as well as the belatacept data that there's going to be a learning curve on how best to combine these novel agents.
“For Phase 2 and Phase 3, we use protocols that may not be ideal for use ultimately in patients or the most effective, but are the ones that are easiest to take them through registration.
“I think once these drugs are out there we'll see how the communal intelligence of our community will come up with the best combination, and I have full confidence that a year or two from now at ATC in the plenary session there will be some investigator who's going to wow us with some wonderful combination again eliminating CNI.”