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In patients undergoing HSCT

ORENCIA is the first and only
FDA-approved option for prophylaxis of acute graft versus host disease (aGVHD)1,2

Indication

ORENCIA is indicated for the prophylaxis of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), in adults and pediatric patients 2 years of age or older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor.

Patients undergoing HSCT are at risk of developing aGVHD, especially patients undergoing HSCT from a mismatched unrelated donor3

PREVALENCE

~5500

HSCT patients are expected to
develop aGVHD each year3

From

30%-70%

of HSCT patients develop
aGVHD—particularly those from
mismatched unrelated donors4

FATALITIES

~16%

of HSCT patients experienced
fatality
caused by aGVHD5

Patients who belong to racial and ethnic minorities may face even greater risk of aGVHD following HSCT from unrelated donors6

This may be due to several factors that impact overall outcome of HSCT, including a lack of donor availability or access to HLA-matched donors and related care.7

Optimally matched (8/8 HLA-matched*) unrelated donors are less available for patients of racial and ethnic minority groups in the United States (US), especially those who are Black or African American.6†

While the likelihood of finding a 7/8 HLA-matched donor is much greater for these patients, it is associated with higher risk of complications and mortality, including aGVHD. Prophylaxis may reduce the risk of aGVHD, making a 7/8 HLA-matched donor a more viable option for many patients from minority backgrounds who cannot find an 8/8 HLA-matched donor.1,4,6

Availability of donors by ethnicity

*Matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci.6

Includes African American, African, Black South or Central American, and Black Caribbean.

Mismatching at only one of these loci: HLA-A, HLA-B, HLA-C, or HLA-DRB1.6

§Based on human HLA data for 10,759,087 adult donors spanning 21 US racial and ethnic groups in the National Marrow Donor Program registry in 2012.6

HLA, human leukocyte antigen.

*Matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci.6

Includes African American, African, Black South or Central American, and Black Caribbean.

Mismatching at only one of these loci: HLA-A, HLA-B, HLA-C, or HLA-DRB1.6

§Based on human HLA data for 10,759,087 adult donors spanning 21 US racial and ethnic groups in the National Marrow Donor Program registry in 2012.6

HLA, human leukocyte antigen.

T-cell activation plays a major role in the mechanism of disease (MOD) of aGVHD8

aGVHD is an immune-triggered process that leads to immune dysregulation and organ dysfunction caused by donor T cells, including damage to the skin, liver, and gastrointestinal tract.9

The interaction of donor T-cells with an antigen-presenting cell promotes the T-cell activation necessary for development of aGVHD.8

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Helping to expand the stem cell donor pool by making efforts to lower the risk of aGVHD in adults and children receiving unrelated-donor stem cell transplants is part of our ongoing commitment to drive health equity and access to our medications.

The mechanism of action (MOA) for ORENCIA inhibits T-cell activation1

ORENCIA has a distinct mechanism of action as an immunomodulator that disrupts T-cell activation—a hallmark of aGVHD pathogenesis.1,8

The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in aGVHD is unknown.1

Ag, antigen; MHC, major histocompatibility complex; TCR, T-cell receptor.

ORENCIA GVHD-1 study design1

The GVHD-1 trial was a multicenter, two-cohort trial evaluating ORENCIA IV (10 mg/kg; 1000 mg maximum dose) in combination with a CNI and MTX, for the prophylaxis of aGVHD. Patients were age 6 years or older who underwent HSCT from a matched or
1-allele—mismatched unrelated donor.

  • Cohort 1: 7/8 HLA matching: an open-label, single-arm study of 43 patients who underwent a 7 of 8 HLA-matched HSCT
  • Cohort 2: 8/8 HLA matching: a randomized (1:1), double-blind, placebo-controlled study of patients who underwent an 8 of 8 HLA-matched HSCT

In both the 7/8 and 8/8 cohorts, ORENCIA was administered as an IV infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation.

CNI, calcineurin inhibitor; HLA, human leukocyte antigen; IV, intravenous; MTX, methotrexate.

View baseline demographics and clinical characteristics for GVHD-1

GVHD-1 efficacy results for ORENCIA, including survival rates1

ORENCIA was studied in patients who received a stem cell transplant from either a matched or 1-allele—mismatched unrelated donor.1

GVHD-1: efficacy at 180 days1

Cohort 1:
7/8 HLA matching
Cohort 2:
8/8 HLA matching
ORENCIA IV + CNI + MTX
(n=43)
ORENCIA IV + CNI + MTX
(n=73)
Placebo + CNI + MTX
(n=69)
Grade III-IV aGVHD-free survivala rate
(95% CI)
95%
(83%, 99%)
87%
(77%, 93%)
Hazard ratio: 0.55
(0.26, 1.18)
75%
(63%, 84%)
Grade II-IV aGVHD-free survivala rate
(95% CI)
53%
(38%, 67%)
50%
(38%, 61%)
Hazard ratio: 0.54
(0.35, 0.83)
32%
(21%, 43%)
Overall
survival rate
(95% CI)
98%
(85%, 100%)
97%
(89%, 99%)
Hazard ratio: 0.33
(0.12, 0.93)
84%
(73%, 91%)

The endpoints/data for the 7 of 8 cohort of ORENCIA-treated patients were an exploratory analysis.

aaGVHD-free survival was measured from the date of transplantation until the onset of documented relative grade of aGVHD, or death by any cause up to Day 180 post-transplantation.

CI, confidence interval.

ORENCIA + CNI + MTX did not significantly improve Grade III-IV aGVHD-free survival versus placebo + CNI + MTX at Day 180 post-transplantation.1

In an exploratory analysis included in the registrational label:

When used with standard of care (SOC)* with unrelated donors, ORENCIA demonstrated efficacy as a prophylactic option for Grade II-IV aGVHD.1

*SOC for this study was CNI and MTX.

GVHD-1 safety summary for ORENCIA1

Serious adverse reactions reported in >5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), hypoxia (5%), and nausea (5%).

Permanent discontinuation due to an adverse reaction occurred in two (1.7%) patients due to one case each of pneumonia and allergic reaction.

Most common AEs1

The most common (≥10%) adverse reactions in the ORENCIA-treated patients were anemia, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, epistaxis, CD4 lymphocytes decreased, hypermagnesemia, and acute kidney injury. See table below.

CMV, cytomegalovirus.

Adverse reactions (≥10%) in patients with aGVHD who received ORENCIA with a difference between arms of >2% compared to placebo in GVHD-11

7/8 Cohort 8/8 Cohort
ORENCIA IV + CNI + MTX
(n=43)
ORENCIA IV + CNI + MTX
(n=73)
Placebo (+CNI and MTX)
All Grades (%) Grade
3 or 4 (%)
All Grades (%) Grade
3 or 4 (%)
All Grades (%) Grade
3 or 4 (%)
Blood and Lymphatic System Disorders
Anemia 56 56 69 69 57 57
CD4 lymphocytes decreased 14 14 14 14 9 9
Vascular Disorders
Hypertension 49 49 43 43 38 38
General Disorders and Administrative Site Conditions
Pyrexia 28 9 19 10 20 4
Infections and Infestations
CMV reactivation/
CMV infection
26 26 32 32 22 22
Pneumonia 19 19 12 12 10 9
Respiratory and Mediastinal Disorders
Epistaxis 12 12 16 16 10 10
Renal and Urinary Disorders
Acute kidney injury 9 7 15 15 10 10
Metabolism and Nutrition Disorders
Hypermagnesemia 5 5 18 18 10 10

ORENCIA GVHD-2 study design1

GVHD-2 was a clinical study using data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study analyzed outcomes of ORENCIA with a CNI + MTX for the prophylaxis of aGVHD vs a CNI + MTX alone in patients 6 years of age or older who underwent HSCT from a 1-allele-mismatched unrelated donor.

The ORENCIA-treated group (n=54) included 42 patients from GVHD-1 in addition to 12 patients from outside of GVHD-1. The comparator group (n=162) was randomly selected in a 3:1 ratio to the ORENCIA-treated group from the CIBMTR registry to create a more robust comparison. Analyses used propensity score matching and inverse probability of treatment weighting to minimize the impact of selection bias.

Adverse event reporting at the individual level was not feasible in GVHD-2 because of limitations of secondary data collected from the CIBMTR registry. Please see Important Safety Information below.

GVHD-2 efficacy results for ORENCIA in overall survival

GVHD-2: efficacy at 180 days1

7/8 HLA matching
ORENCIA IV + CNI + MTX Placebo (+CNI and MTX)
Overall
survival rate
(95% CI)
98%
(78%, 100%)
75%
(67%, 82%)

When used with SOC, ORENCIA demonstrated improved overall survival rates compared to SOC alone.1

Dosing in prophylaxis of aGVHD in adults and pediatric patients aged 2 years and older1

Antiviral prophylaxis treatment

  • Before administering ORENCIA, administer recommended antiviral prophylactic treatment for Epstein-Barr virus (EBV) reactivation, and continue for 6 months following HSCT. In addition, consider prophylactic antivirals for CMV infection/reactivation during treatment and for 6 months following HSCT

Intravenous dosing regimen

  • For patients 6 years and older, administer ORENCIA 10 mg/kg (maximum dose of 1000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation
  • For patients 2 to less than 6 years old, administer ORENCIA 15 mg/kg as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by 12 mg/kg as an intravenous infusion over 60 minutes on Days 5, 14, and 28 after transplantation

Important Safety Information
for ORENCIA® (abatacept)

Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors: Concurrent therapy with ORENCIA and a TNF antagonist is not recommended. In controlled clinical trials, adult moderate to severe rheumatoid arthritis (RA) patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs 43%) and serious infections (4.4% vs 0.8%) compared to patients treated with only TNF antagonists, without an important enhancement of efficacy. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended.

Hypersensitivity: There were 2 cases (<0.1%; n=2688) of anaphylaxis reactions in clinical trials with adult RA patients treated with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in <0.9% of patients. There was one case of a hypersensitivity reaction with ORENCIA in pJIA clinical trials (0.5%; n=190). In postmarketing experience, fatal anaphylaxis following the first infusion of ORENCIA and life-threatening cases of angioedema have been reported. Angioedema has occurred as early as after the first dose of ORENCIA, but also has occurred with subsequent doses. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days). Appropriate medical support measures for treating hypersensitivity reactions should be available for immediate use. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately and permanently discontinued, with appropriate therapy instituted.

Infections: Serious infections, including sepsis and pneumonia, were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which, in addition to their underlying disease, could further predispose them to infection. Caution should be exercised in patients with a history of infection or underlying conditions which may predispose them to infections. Treatment with ORENCIA should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis and viral hepatitis in accordance with published guidelines, and if positive, treated according to standard medical practice prior to therapy with ORENCIA.

Immunizations: Prior to initiating ORENCIA in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines. Live vaccines should not be given concurrently with ORENCIA or within 3 months after discontinuation. ORENCIA may blunt the effectiveness of some immunizations. In addition, it is unknown if the immune response of an infant who was exposed in utero to abatacept and subsequently administered a live vaccine is impacted. Risks and benefits should be considered prior to vaccinating such infants.

Increased Risk of Adverse Reactions When Used in Patients with Chronic Obstructive Pulmonary Disease (COPD): In Study V, adult COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. In the study, 97% of COPD patients treated with ORENCIA developed adverse events versus 88% treated with placebo. Respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to those on placebo (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)]. Use of ORENCIA in patients with COPD should
be undertaken with caution, and such
patients monitored for worsening of their respiratory status.

Immunosuppression: In clinical trials in adult RA patients, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. There have been reports of malignancies, including skin cancer in
patients receiving ORENCIA. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.

Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic Stem Cell Transplant (HSCT): Post-Transplant Lymphoproliferative Disorder (PTLD) occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 4 patients (3.4%) experienced PTLD. All the PTLD events were associated with Epstein-Barr virus (EBV) infection. The range of time to onset of the event was 49 to 89 days post-transplant. Monitor patients for EBV reactivation in accordance with institutional practices. Before administering ORENCIA, provide recommended prophylaxis for EBV infection and continue for 6 months post-transplantation to prevent EBV-associated PTLD. Cytomegalovirus (CMV) invasive disease occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 7% (n=8) experienced CMV invasive diseases up to day 225 post-transplant. The median time to onset of the event was 91 days post-transplant. CMV invasive diseases predominantly involved the gastrointestinal tract. Monitor patients for CMV infection/reactivation for 6 months post-transplant regardless of the results of donor and recipient pre-transplant CMV serology. Consider prophylaxis for CMV infection/reactivation during treatment and for six months following HSCT.

Blood Glucose Testing: ORENCIA for intravenous administration contains maltose, which may result in falsely elevated blood glucose readings on the day of infusion when using blood glucose monitors with test strips utilizing glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). Consider using monitors and advising patients to use monitors that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase or glucose hexokinase test methods. ORENCIA for subcutaneous (SC) administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

Pregnancy: There are no adequate and well-controlled studies of ORENCIA use in pregnant women and the data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients by calling 1-877-311-8972.

Lactation: There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept.

Most Serious Adverse Reactions: In controlled clinical trials, adult RA patients experienced serious infections (3% ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1% placebo). In the GVHD-1 study, serious adverse reactions reported in >5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), hypoxia (5%), and nausea (5%).

Malignancies: The overall frequency of malignancies was similar between adult RA patients treated with ORENCIA or placebo. However, more cases of lung cancer were observed in patients treated with ORENCIA (0.2%) than those on placebo (0%). A higher rate of lymphoma was seen compared to the general population; however, patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of ORENCIA in the development of malignancies in humans is unknown.

Most Frequent Adverse Events (≥10%): Headache, upper respiratory tract infection, nasopharyngitis, and nausea were the most commonly reported adverse events in the adult RA clinical studies. Other events reported in ≥5% of pJIA patients were diarrhea, cough, pyrexia, and abdominal
pain. In general, the adverse events in pediatric pJIA and adult PsA patients were similar in frequency and type to those seen in adult RA patients. The most frequent adverse reactions of all grades reported in ≥10% of patients with aGVHD who received ORENCIA with a difference of ≥2% for the 7/8 cohort, 8/8 cohort ORENCIA arm, and 8/8 cohort placebo arm, respectively, were anemia (56%, 69%, and 57%), CD4 lymphocytes decreased (14%, 14%, and 9%), hypertension (49%, 43%, and 38%), pyrexia (28%, 19%, and 20%), CMV reactivation/CMV infection (26%, 32%, and 22%), pneumonia (19%, 12%, and 10%), epistaxis (12%, 16%, and 10%), acute kidney injury (9%, 15%, and 10%), and hypermagnesemia (5%, 18%, 10%).

Incidence rates of grade 3 or 4 adverse reactions were the same as incidence rates of all grades, with the exception of grade 3 or 4 pyrexia in all arms (9% [7/8 cohort], 10% [8/8 cohort, ORENCIA arm], and 4% [8/8 cohort, placebo arm]), pneumonia in the 8/8 cohort placebo arm (9%) and acute kidney injury in the 7/8 cohort ORENCIA arm (7%). Clinically relevant adverse reactions in <10% of patients who received ORENCIA in combination with calcineurin inhibitor and methotrexate in Study GVHD-1 included EBV reactivation.

Note concerning ORENCIA administration options: ORENCIA may be administered as an intravenous infusion only for patients 6 years of age and older. PJIA patients may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. ORENCIA may only be administered as an intravenous (IV) infusion for the prophylaxis of aGVHD in patients undergoing HSCT. The safety and effectiveness of ORENCIA have not been established in pediatric patients younger than 2 years of age for prophylaxis of aGVHD.

Please click here for Full Prescribing Information  

References: 1. ORENCIA [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2. U.S. Food and Drug Administration accepts for Priority Review Bristol Myers Squibb's application for Orencia (abatacept) for the prevention of acute graft versus host disease (aGvHD). News release. Bristol Myers Squibb. August 23, 2021. Accessed December 8, 2021. https://news.bms.com/news/corporate-financial/2021/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Bristol-Myers-Squibbs-Application-for-Orencia-abatacept-for-the-Prevention-of-Acute-Graft-Versus-Host-Disease-aGvHD/default.aspx. 3. Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis. 2007;2:35. 4. Leukemia & Lymphoma Society. Graft-versus-host disease. Accessed December 8, 2021. https://www.lls.org/booklet/graft-versus-host-disease. 5. Yu J, Parasuraman S, Shah A, Weisdorf D. Mortality, length of stay and costs associated with acute graft-versus-host disease during hospitalization for allogeneic hematopoietic stem cell transplantation. Curr Med Res Opin. 2019;35(6):983-988. 6. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339-348. 7. Majhail NS, Nayyar S, Burton Santibañez ME, Murphy EA, Denzen EM. Racial disparities in hematopoietic cell transplantation in the United States. Bone Marrow Transplant. 2012;47(11):1385-1390. 8. Leveque L, Le Texier L, Lineburg KE, Hill GR, MacDonald KPA. Autophagy and haematopoietic stem cell transplantation. Immunol Cell Biol. 2015;93(1):43-50. 9. Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute graft versus host disease: a comprehensive review. Anticancer Res. 2017;37(4):1547-1555.