Older Immunosuppressant as Good As Newer One, But 10 Times Cheaper

Pam Harrison

November 18, 2019

WASHINGTON, DC — The widespread replacement of the immunosuppressant azathioprine (AZA) with mycophenolate mofetil (MMF) at a time when only the old formulation of cyclosporine (CsA) was available continues to cost kidney transplant centers at least 10 times more than they should be paying, with absolutely no evidence to indicate that MMF is superior to AZA, new research indicates.

Paolo Cravedi, MD, PhD, reported the findings of the ATHENA trial here at Kidney Week 2019: American Society of Nephrology Annual Meeting.

"MMF virtually replaced AZA worldwide," as a result of the two large approval trials for MMF in the mid-1990s that showed it was associated with a reduced risk of acute rejection compared with AZA in kidney transplant recipients, Cravedi explained during a press briefing. But those trials were conducted using the older formulation of CsA as part of the immunosuppressive regimen.

But, as MMF was taking over the immunosuppressive market, a new, more powerful formulation of CsA, Neoral (Sandimmune), was also introduced, said Cravedi, of the Icahn School of Medicine at Mount Sinai, New York City.

Multiple studies subsequently indicated that using standard-doses of Neoral, a more stable microemulsion formulation of CsA, together with AZA was equivalent in terms of both patient and graft survival compared with the combination of MMF and the same formulation of CsA, including one published by Cravedi and colleagues, he pointed out.

Nevertheless, the equivalency between AZA and MMF has remained largely unknown in the context of more contemporary immunosuppressive regimens, where efforts are made to minimize the doses of immunosuppression in order to minimize associated risk, he explained.

Thus, the ATHENA trial was designed to assess the safety and efficacy of AZA vs MMF.

Commenting on the findings, press briefing chair Pascale Lane, MD, noted that having lived through this transitional period, there were all sorts of anecdotal reports of the benefits of MMF at that time.

"People thought it was going to be better [than AZA] for preventing chronic rejection, among any number of things, which have not panned out over the years," observed Lane, who is professor of pediatrics and pediatric nephrology, University of Oklahoma Health Sciences Center, Oklahoma City.

"AZA represents a valuable, less expensive, alternative to MMF," Cravedi and colleagues conclude.

Bottom Line: No Difference Between AZA and MMF

ATHENA assessed AZA versus MMF in 233 kidney transplant recipients on a steroid-free, low-dose CsA regimen following induction with low-dose thymoglobulin (Sanofi Genzyme) plus basiliximab (Simulect, Novartis).

"Patients underwent serial biopsies to check the health of their graft, and at 1 year, those who had stable graft function and no infiltrates in their kidney underwent further reduction of their cyclosporine, where CsA doses were tapered to half of the initial dose," Cravedi observed.

The primary endpoint of the study was chronic allograft nephropathy or chronic rejection at 3 years.

"The bottom-line finding was that there was no difference between AZA and MMF even when using low doses of cyclosporine and no steroids," he reported.

At 3 years, 32.4% of patients on AZA had developed chronic allograft nephropathy compared with 31.9% of those on MMF.

Some 21.1% of AZA patients had biopsy-proven acute graft rejection compared with 18.5% of those on MMF, while 7% of AZA patients compared with 9.2% of MMF patients had evidence of subclinical acute graft rejection at the 1-year surveillance biopsy.

The estimated glomerular filtration rate (eGFR) and safety profiles of both regimens were also similar at 3 years. Tapering of the CsA dose was also associated with stable graft function and only two patients, one in each arm, experienced acute graft rejection on dose tapering.

"In kidney transplant recipients on low-dose CsA and no steroids, AZA is associated with a similar incidence of chronic allograft nephropathy, acute rejections, and a similar eGFR and safety profile as MMF," Cravedi emphasized.

Substituting AZA With MMF Cost Kidney Transplant Community $1 Billion

However, the cost differential between the two regimens is over 10-fold higher for an MMF-based regimen — at over $4000 a year for each transplant recipient — compared with approximately $500 a year for an AZA-based regimen.

Indeed, Cravedi and colleagues estimate that the impact of switching from AZA, when the old formulation of CsA was still the only one available, to MMF has cost the transplant community over $1 billion for kidney transplant recipients alone.

Commenting on the findings, co-investigator Giuseppe Remuzzi, MD, Mario Negri Institute for Pharmacological Research, Bergamo, Italy, pointed out that the acute rejection rates in both approval studies evaluating MMF were approximated 50%.

"This has always been really bizarre to me because in Italy, with AZA, our acute rejection rates have not been more than 30%, yet MMF replaced AZA on the basis of these two studies that showed an unbelievably high number of acute rejections," he told the press briefing.

Italy and UK Continue to Use AZA as Cornerstone of Immunosuppression

Perhaps needless to say, transplant centers in Italy have continued to use AZA as a cornerstone in their immunosuppressive regimens and have no plans to introduce other agents, including tacrolimus, as it has a very narrow therapeutic window and is more complicated to use than CsA, Remuzzi explained.

Lane also noted that there are significant gastrointestinal side effects with MMF. "So if we have a child who just can't tolerate MMF because of the diarrhea, we switch them back to AZA and they do just fine."

Cravedi added that the National Health Service in the United Kingdom also promotes the use of AZA based on the fact that there are no demonstrable differences in graft outcomes between AZA and MMF and because AZA is so much cheaper than MMF. 

Kidney Week 2019. Abstract #FR-OR135. Presented November 8, 2019.

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