Orencia (abatacept, CTLA-4-IgG1) was developed by Bristol-Myers Squibb and is approved for the treatment of rheumatoid arthritis. It also is used to treat psoriatic arthritis and juvenile idiopathic arthritis.

The medicine is currently being investigated for the treatment of patients with non-severe relapsing granulomatosis with polyangiitis (GPA), a type of ANCA vasculitis.

How Orencia works

Orencia is a recombinant fusion protein that consists of the extracellular ligand-binding domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc region of human immunoglobulin G1 (IgG1).

Orencia works by selectively modulating a key costimulatory signal, which is required for the full activation of specialized immune cells, called T-cells, that produce the CD28 protein.

The full activation of T-cells requires two signals provided by antigen-presenting cells (APCs). The first signal is the recognition of a specific antigen by a T-cell receptor, while the second (costimulatory) signal involves the binding of CD80 and CD86 molecules found on the surface of APCs to the CD28 receptor on T-cells. Orencia selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86, therefore blocking their binding to the CD28 receptor on T-cells.

Studies conducted in vitro and in animal models demonstrate that Orencia modulates T-cell-dependent antibody responses and inflammation. In vitro, it attenuated the activation of human T-cells as measured by a decreased proliferation and cytokine production. (Cytokines are cell-signaling molecules that play an important role in immunity).

Orencia in clinical trials

An open-label trial of Orencia injected into the bloodstream was conducted in 20 patients with non-severe relapsing GPA. The results showed that Orencia was well-tolerated and was associated with a high frequency of disease remission and prednisone discontinuation. (Prednisone is a corticosteroid that is often used to control the symptoms of GPA).

Prednisone up to 30 mg daily was permitted within the first two months of the study, and patients on other immune system suppressants such as methotrexate, azathioprine, or mycophenolate mofetil continued these agents. Patients remained on the study until common closing or early termination.

Of the 20 patients, 18 (90 percent) had a disease improvement, 16 (80 percent) achieved disease remission, and 14 (70 percent) reached common closing. Eleven of the 15 patients on prednisone were able to discontinue the drug. Six patients met the criteria for early termination due to increased disease activity; three of the six patients achieved remission and relapsed. Nine severe adverse events occurred in seven patients, including seven infections that were successfully treated.

A multicenter, randomized, double-blind, placebo-controlled Phase 3 trial (NCT02108860) called ABROGATE is currently recruiting up to 150 participants at 23 locations across the U.S., Canada, Ireland, and the U.K.

The trial aims to further evaluate the effectiveness of Orencia in achieving sustained corticosteroid-free remission in patients with relapsing non-severe GPA. Patients who enter the trial will be maintained on a stable dose of their immunosuppressive agent, which may include methotrexate, azathioprine, or mycophenolate, and will undergo a blinded randomization to receive either Orencia (125 mg) or placebo administered as an injection under the skin once a week. Patients will additionally receive 30 mg of daily prednisone that will then be tapered to zero using a standardized tapering schedule. Participants will continue on study treatment (Orencia or placebo) for a minimum of 12 months unless they experience a disease relapse or disease flare.

Participants who experience a non-severe disease relapse, non-severe disease worsening, or who have not achieved remission by month 6, will have the option of taking part in an open-label trial period whereby they will receive Orencia in conjunction with their maintenance immunosuppressive agent and a standardized corticosteroid taper. Patients with a severe disease relapse or severe disease worsening will have met criteria for early termination and will be removed from the study.  Patients will remain on the trial until reaching criteria for early termination or until common closing (12 months after randomization of the final patient). After common closing or early termination, patients will be treated with best medical judgment and undergo a post-treatment safety visit three months after coming off the trial.

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