Testing a New Tool for Improving Long-Term Outcomes in Heart Transplantation

Survival rates for heart transplantation have improved dramatically since the early 1980s, when calcineurin inhibitors (CNIs) emerged as the first drugs to effectively prevent acute cellular rejection. Such medications, however, offer less protection against chronic rejection associated with the development of donor specific antibodies (DSA)—a major factor in long-term allograft failure. They can also lead to nephrotoxic and other side effects that often damage the graft and otherwise undermine patients’ health.

“Our one-year survival in heart transplantation is over 90 percent, but we have not made great progress in improving late outcomes,” notes Marlena Habal, MD, a cardiologist and transplant immunologist at NYU Langone Health. “Median survival is only 12 to 15 years, largely due to the limitations of our immunosuppression regimens.”

To help overcome those flaws, Dr. Habal is leading a groundbreaking study of a newer type of immunosuppressant: belatacept, whose track record in kidney transplantation offers hope of similar benefits in the cardiac realm.

Encouraging Results Spur Hopes for Broader Successes

CNIs such as cyclosporine and tacrolimus broadly suppress immune activation by blocking signaling downstream of the T-cell receptor. Belatacept, by contrast, is a co-stimulation blocker, selectively inhibiting a second activation pathway—the CD80/CD86 signals between antigen-presenting cells and T cells.

The FDA approved belatacept for kidney transplantation in 2011, after two phase 3 clinical trials showed that the drug, in combination with mycophenolate and corticosteroids, resulted in better renal function and equivalent patient and allograft survival compared to a cyclosporine-based regimen.

Later, switching patients to belatacept after initial treatment with CNIs was shown to reduce preexisting and de novo DSA as well as the incidence of antibody-mediated rejection. At seven years post-transplant, kidney recipients on belatacept had a 43 percent lower risk of death or graft loss than those on cyclosporin.

Inspired by these findings, Dr. Habal and her team began investigating belatacept as a tool for desensitizing end-stage heart failure patients whose pre-existing DSA would typically make them poor candidates for cardiac transplantation. They administered the medication in concert with transient proteasome inhibitors, an approach that enabled several such patients to successfully receive new hearts.

“Like some other groups, we’ve been using belatacept, in a niche setting, with very good results,” Dr. Habal explains. “Now, we want to develop a harmonized protocol that can benefit a broader range of heart transplant recipients.”

Exploring Belatacept’s Utility for Non-Sensitized Patients

The new study, funded by the National Institute of Allergy and Infectious Diseases, is a phase 2, multicenter, open-label clinical trial. A total of 66 primary heart transplant recipients will be randomized to receive either standard-of-care, tacrolimus-based immunosuppression, or a belatacept-based regimen with gradual withdrawal from the CNI over nine months post-transplant. Both study arms will receive CellCept (mycophenolate mofetil) or Myfortic (mycophenolate sodium) and corticosteroids.

Among the exclusion criteria for the trial is desensitization prior to transplant. “This study focuses on people without pre-existing DSA,” Dr. Habal says. “It’s for your standard heart transplant recipient, to the extent that such a person exists.”

The primary outcome measurement is the proportion of participants who experience acute cellular rejection, hemodynamic compromise rejection in the absence of biopsy, or a composite endpoint of histological rejection, re-transplantation, or death to 18 months post-transplant. Secondary endpoints include the proportion of patients who are free from any detection of de novo DSA or antibody-mediated rejection, as well as the incidence of kidney problems, serious infections, and malignancies.

“Life expectancy after heart transplantation has been stagnant for the past 15 years or so,” observes Alex Reyentovich, MD, director of the Heart Failure Program and medical director of the Heart Transplant Program at NYU Langone. “Hopefully, this trial will help extend survival not only for the participants, but for patients around the world.”