Today, the U.S. Food and Drug Administration approved Orencia (abatacept) for the prophylaxis (prevention) of acute graft versus host disease (aGVHD), a condition that occurs when donor bone marrow or stem cells attack the graft recipient, in combination with certain immunosuppressants. Orencia may be used in adults and pediatric patients two years of age or older undergoing hematopoietic stem cell transplantation (commonly known as bone marrow transplantation or stem cell transplantation) from an unrelated donor.
This is the first FDA drug approval for aGVHD prevention and incorporates real world evidence (RWE) as one component of the determination of clinical effectiveness. RWE is clinical evidence regarding the usage and potential benefits, or risks, of a medical product derived from analysis of real world data – i.e., data relating to patient health status and/or the delivery of health care routinely collected data from a variety of sources, including registry data. There are significant ongoing efforts at the FDA to incorporate use of high-quality RWE to support regulatory decision-making.
“Acute graft versus host disease can affect different parts of the body and become a serious post-transplant complication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “By potentially preventing the disease, more patients may successfully undergo bone marrow or stem cell transplantation with fewer complications.”
Acute GVHD is a potentially fatal complication that can occur after stem cell transplantation when the donor’s immune cells (the graft) view the recipient’s body (the host) as foreign, and the donated cells attack the body. The chances of developing aGVHD increase when the donor and recipient are not related or are not a perfect match.
The safety and efficacy of Orencia in combination with immunosuppressant therapy in patients age six years and older who underwent stem cell transplantation from a matched or mismatched unrelated donor were evaluated in two separate studies.
One study, GVHD-1, was a double-blind, placebo-controlled trial of 186 patients who underwent stem cell transplantation from a matched unrelated donor and randomly received Orencia or a placebo in combination with the immunosuppressive drugs. The study measured severe (grade III-IV) aGVHD-free survival, overall survival and moderate-severe (grade II-IV) aGVHD-free survival six months after transplantation. While severe aGVHD-survival was not significantly improved in patients who received Orencia (87%) compared to patients who received a placebo (75%), patients who received Orencia saw a 97% overall survival rate compared to 84% for patients who received a placebo. For moderate-severe aGVHD-free survival, patients who received Orencia saw a 50% rate compared to 32% for patients who received a placebo.
Additional evidence of effectiveness was provided by GVHD-2, a registry-based clinical study conducted using real world data from the Center for International Blood and Marrow Transplant Research in patients who underwent stem cell transplantation from a mismatched unrelated donor. This study analyzed outcomes of 54 patients treated with Orencia for the prevention of aGVHD, in combination with standard immunosuppressive drugs, versus 162 patients treated with standard immunosuppressive drugs alone. The study measured overall survival six months after transplantation. Patients who received Orencia saw a 98% overall survival rate compared to 75% for patients who received standard immunosuppression alone.
The most common side effects of Orencia for prevention of aGVHD include anemia, hypertension, cytomegalovirus (CMV) reactivation/CMV infection, fever, pneumonia, nosebleed, decreased levels of specific white blood cells called CD4 lymphocytes, increased levels of magnesium in the blood and acute kidney injury. Patients who receive Orencia should be monitored for Epstein-Barr virus reactivation in accordance with institutional practices and receive preventative medication for Epstein-Barr virus infection before starting treatment and for six months post-transplantation. Patients should also be monitored for CMV infection/reactivation for six months post-transplant.
Orencia received Breakthrough, Orphan Drug and Priority Review designations for this indication. Development of this product was partially supported by the FDA’s Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.
Orencia was originally approved by the FDA in 2005 for the treatment of adult rheumatoid arthritis. Orencia is also approved for the treatment of polyarticular juvenile idiopathic arthritis and adult psoriatic arthritis.
The FDA granted approval of Orencia to Bristol Myers Squibb.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Health Canada, Swissmedic and MOH (Israel’s Ministry of Health). The application reviews are ongoing at the other regulatory agencies.