CLINICAL STUDIES

Adult Rheumatoid Arthritis

Description of Clinical Studies of Intravenous ORENCIA for the Treatment of Patients with RA

The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization, and Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in Studies I, II, III, IV, and VI.

Study I (NCT00279760) evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept.
In Study II (NCT00162266) and Study III (NCT00048568), the efficacy of ORENCIA were assessed in patients with an inadequate response to MTX and who were continued on their stable dose of MTX.
In Study IV (NCT00048581), the efficacy of ORENCIA was assessed in patients with an inadequate response to a TNF antagonist, with the TNF antagonist discontinued prior to randomization; other DMARDs were permitted.
Study V (NCT00048932) primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions.
In Study VI (NCT00122382), the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo.

Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg.

Description of Clinical Studies of Subcutaneous or Intravenous ORENCIA for the Treatment of Patients with Adult RA

The efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1 (NCT00559585), which was a randomized, double-blind, double-dummy, non-inferiority study that compared ORENCIA administered subcutaneously to ORENCIA administered intravenously in 1457 patients with moderate to severely active RA, receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). In Study SC-1, patients were randomized with stratification by body weight (<60 kg, 60 to 100 kg, >100 kg) to receive (1) ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or (2) ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of MTX from the day of randomization.

Clinical Response in Adult RA Patients

The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 9. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III.

In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus MTX in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.

In Study VI, a greater proportion of patients treated with ORENCIA plus MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with MTX plus placebo (Table 9). Of patients treated with ORENCIA plus MTX who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.

In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of −7.5%. As shown in Table 10, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 9. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown).

Table 9: Clinical Responses in Controlled Trials in Patients with RA
Percent of Patients
Intravenous Administration								Subcutaneous or Intravenous Administration
Inadequate Response to DMARDs		Inadequate Response to Methotrexate (MTX)		Inadequate Response to TNF Antagonists		MTX-Naive		Inadequate Response to MTX
Study I		Study III		Study IV		Study VI		Study SC-1
• p<0.05, ORENCIA (ORN) vs placebo (PBO) or MTX. ^†p<0.01, ORENCIA vs placebo or MTX. ^‡p<0.001, ORENCIA vs placebo or MTX. ^§95% CI: −4.2, 4.8 (based on prespecified margin for non-inferiority of −7.5%). ^a10 mg/kg. ^bDosing based on weight range [ see* Dosage and Administration (2.1) ]* . ^cMajor clinical response is defined as achieving an ACR 70 response for a continuous 6-month period. ^dRefer to text for additional description of remaining joint activity. ^ePer protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively.
Response Rate	ORN ^a n=32	PBO n=32	ORN ^b +MTX n=424	PBO +MTX n=214	ORN ^b+ DMARDs n=256	PBO + DMARDs n=133	ORN ^b +MTX n=256	PBO +MTX n=253	ORN ^e SC +MTX n=693	ORN ^e IV +MTX n=678
ACR 20
Month 3	53%	31%	62% ^‡	37%	46% ^‡	18%	64%•	53%	68%	69%
Month 6	NA	NA	68% ^‡	40%	50% ^‡	20%	75% ^†	62%	76% ^§	76%
Month 12	NA	NA	73% ^‡	40%	NA	NA	76% ^‡	62%	NA	NA
ACR 50
Month 3	16%	6%	32% ^‡	8%	18% ^†	6%	40% ^‡	23%	33%	39%
Month 6	NA	NA	40% ^‡	17%	20% ^‡	4%	53% ^‡	38%	52%	50%
Month 12	NA	NA	48% ^‡	18%	NA	NA	57% ^‡	42%	NA	NA
ACR 70
Month 3	6%	0	13% ^‡	3%	6%•	1%	19% ^†	10%	13%	16%
Month 6	NA	NA	20% ^‡	7%	10% ^†	2%	32% ^†	20%	26%	25%
Month 12	NA	NA	29% ^‡	6%	NA	NA	43% ^‡	27%	NA	NA
Major Clinical Response ^c	NA	NA	14% ^‡	2%	NA	NA	27% ^‡	12%	NA	NA
DAS28-CRP <2.6 ^d
Month 12	NA	NA	NA	NA	NA	NA	41% ^‡	23%	NA	NA

The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 10 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients.

Table 10: Components of ACR Responses at 6 Months in Adult Patients with RA
Intravenous Administration								Subcutaneous or Intravenous Administration
Inadequate Response to MTX				Inadequate Response to TNF Antagonists				Inadequate Response to MTX
Study III				Study IV				Study SC-1 ^c
^†p<0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline. ^‡p<0.001, ORENCIA vs placebo, based on mean percent change from baseline. ^aVisual analog scale: 0 = best, 100 = worst. ^bHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. ^cSC-1 is a non-inferiority study. Per protocol data is presented in table.
ORN +MTX n=424		PBO +MTX n=214		ORN +DMARDs n=256		PBO +DMARDs n=133		ORN SC +MTX n=693		ORN IV +MTX n=678
Component (median)	BL	6 M	BL	6 M	BL	6 M	BL	6 M	BL	6 M	BL	6 M
Number of tender joints (0-68)	28	7 ^‡	31	14	30	13 ^‡	31	24	27	5	27	6
Number of swollen joints (0-66)	19	5 ^‡	20	11	21	10 ^‡	20	14	18	4	18	3
Pain ^a	67	27 ^‡	70	50	73	43 ^†	74	64	71	25	70	28
Patient global assessment ^a	66	29 ^‡	64	48	71	44 ^‡	73	63	70	26	68	27
Disability index ^b	1.75	1.13 ^‡	1.75	1.38	1.88	1.38 ^‡	2.00	1.75	1.88	1.00	1.75	1.00
Physician global assessment ^a	69	21 ^‡	68	40	71	32 ^‡	69	54	65	16	65	15
CRP (mg/dL)	2.2	0.9 ^‡	2.1	1.8	3.4	1.3 ^‡	2.8	2.3	1.6	0.7	1.8	0.7

The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III.

Figure 1: Percent of Patients Achieving ACR 50 Response by Visit• (Study III)

Referenced Image
•The same patients may not have responded at each time point.

The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85—SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%.

Radiographic Response in Adult RA Patients

In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/MTX slowed the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 11.

Table 11: Mean Radiographic Changes in Study III ^aand Study VI ^b
Parameter	ORENCIA/MTX	Placebo/MTX	Differences	P-value ^d
^aPatients with an inadequate response to MTX. ^bMTX-naive patients. ^cPatients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX. ^dBased on a nonparametric ANCOVA model.
Study III
First Year
TSS	1.07	2.43	1.36	<0.01
ES	0.61	1.47	0.86	<0.01
JSN score	0.46	0.97	0.51	<0.01
Second Year
TSS	0.48	0.74 ^c
ES	0.23	0.22 ^c
JSN score	0.25	0.51 ^c
Study VI
First Year
TSS	0.6	1.1	0.5	0.04

In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/MTX and 65% of patients initially randomized to placebo/MTX were evaluated radiographically at Year 2. As shown in Table 11, progression of structural damage in ORENCIA/MTX-treated patients was further reduced in the second year of treatment.

Following 2 years of treatment with ORENCIA/MTX, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/MTX-treated patients had no progression during the first year compared to 45% of placebo/MTX-treated patients. In their second year of treatment with ORENCIA/MTX, more patients had no progression than in the first year (65% vs 56%).

Physical Function Response and Health-Related Outcomes in Adult RA Patients

Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus MTX in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous ORENCIA administration. The results from Studies II and III are shown in Table 12. Similar results were observed in Study V compared to placebo and in Study VI compared to MTX. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years.

Table 12: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) in Adult Patients with RA
Inadequate Response to Methotrexate
Study II		Study III
••• p<0.001, ORENCIA vs placebo. ^a10 mg/kg. ^bDosing based on weight range [ see* Dosage and Administration (2.1) ]* . ^cModified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. ^dHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
HAQ Disability Index	ORENCIA ^a +MTX (n=115)	Placebo +MTX (n=119)	ORENCIA ^b +MTX (n=422)	Placebo +MTX (n=212)
Baseline (Mean)	0.98 ^c	0.97 ^c	1.69 ^d	1.69 ^d
Mean Improvement Year 1	0.40 ^c,•••	0.15 ^c	0.66 ^d,•••	0.37 ^d

Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

Polyarticular Juvenile Idiopathic Arthritis

Polyarticular Juvenile Idiopathic Arthritis - Intravenous Administration

The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1 (NCT00095173), a three-part study including an open-label extension in pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). Patients 6 to 17 years of age (n=190) with moderately to severely active pJIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had JIA subtypes that at disease onset included oligoarticular (16%), polyarticular (64%; 20% were rheumatoid factor positive), and systemic JIA without systemic manifestations (20%). At study entry, 74% of patients were receiving MTX (mean dose, 13.2 mg/m ²per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX treatment during the study).

In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1,000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.

At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.

During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients (intravenous) experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on intravenous ORENCIA was less than one-third than that for patients withdrawn from intravenous ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received intravenous ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.

Polyarticular Juvenile Idiopathic Arthritis - Subcutaneous Administration

ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2 (NCT01844518), a 2-period, open-label study that included pediatric patients 2 to 17 years of age (n=205). Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD. The JIA patient subtypes at study entry included polyarticular (79%; 22% were rheumatoid factor positive), extended and persistent oligoarticular (14%), enthesitis-related arthritis (1%), and systemic JIA without systemic manifestations (2%). Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL). At study entry, 80% of patients were receiving MTX and remained on a stable dose of MTX. Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen. The primary objective of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see Clinical Pharmacology (12.3) ] .

JIA ACR 30/50/70 responses assessed at 4 months in the 2- to 17-year-old patients treated with subcutaneous ORENCIA were consistent with the results from intravenous ORENCIA in Study JIA-1.

Psoriatic Arthritis

The efficacy of ORENCIA was assessed in 594 adult patients (18 years and older) with psoriatic arthritis (PsA), in two randomized, double-blind, placebo-controlled studies (Studies PsA-I [NCT00534313] and PsA-II [NCT01860976]). Patients had active PsA (≥3 swollen joints and ≥3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF antagonists previously.

During the initial 24-week, double-blind period of Study PsA-I, 170 patients were randomized to receive one of four intravenous treatments on Days 1, 15, 29, and then every 28 days (there was no escape during the 24-week period):

Placebo
ORENCIA 3 mg/kg
ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg (weight-range-based dosing), or
ORENCIA 30 mg/kg on Days 1 and 15 followed by weight range-based ORENCIA dosing (i.e., 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg).

After the 24-week double blind period in Study PsA-I, patients received open-label intravenous ORENCIA every 28 days.

Patients were allowed to receive stable doses of concomitant MTX, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving MTX. At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively.

In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of subcutaneous placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label subcutaneous ORENCIA 125 mg weekly. Patients were allowed to receive stable doses of concomitant MTX, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At randomization, 60% of patients were receiving MTX. The baseline disease characteristics included presence of joint erosion on X-rays in 84% (341/407) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/421]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label subcutaneous ORENCIA 125 mg weekly.

The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).

Clinical Response in Adults with PsA

A greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with intravenous ORENCIA (weight-range-based dosing as described above) compared to placebo in Study PsA-I and a greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with subcutaneous 125 mg compared to placebo in Study PsA-II at Week 24. Responses were seen regardless of prior TNF antagonist treatment and regardless of concomitant non-biologic DMARD treatment. The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA‑I and PsA-II are presented in Table 13 below.

Table 13: Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-II ^a
PsA-I		PsA-II
• p<0.05 versus placebo. ^aPatients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders. ^bWeight range-based intravenous dosing: ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg.
ORENCIA Weight-Range-Based Intravenous Dosing ^b N=40	Placebo N=42	ORENCIA 125 mg Subcutaneous N=213	Placebo N=211
ACR 20	47.5%•	19.0%	39.4%•	22.3%
ACR 50	25.0%	2.4%	19.2%	12.3%
ACR 70	12.5%	0%	10.3%	6.6%

The percentage of patients in PsA-II achieving ACR 20 response through Week 24 is shown below in Figure 2.

Figure 2: Percent of Patients Achieving ACR 20 Response ^ain PsA-II Study Through Week 24 (Day 169)

Results were generally consistent across the ACR components in Study PsA-I and PsA-II.

Improvements in enthesitis and dactylitis were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II.

Physical Function Response in Adults with PsA

In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA weight range-based dosing as described above (45%) vs. placebo (19%) of 26.1 (95% confidence interval: 6.8, 45.5). In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%). There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs. placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01).

Prophylaxis of Acute Graft versus Host Disease

Study GVHD-1

The efficacy of ORENCIA, in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), for the prophylaxis of Acute Graft Versus Host Disease (aGVHD), was evaluated in a multicenter, two cohort clinical study (GVHD-1, NCT01743131) in patients age 6 years and older who underwent hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor (URD). The two cohorts in GVHD-1 included:

an open-label, single-arm study of 43 patients who underwent a 7 of 8 Human Leukocyte Antigen (HLA)-matched HSCT (7 of 8 cohort); and
a randomized (1:1), double-blind, placebo-controlled study of patients who underwent an 8 of 8 HLA-matched HSCT who received ORENCIA or placebo in combination with a CNI and MTX (8 of 8 cohort).

In both the 7/8 and 8/8 cohorts, ORENCIA was administered at a dose of 10 mg/kg (1,000 mg maximum dose) as an intravenous infusion over 60 minutes, beginning on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation. Baseline demographic and clinical characteristics of both the 7 of 8 and 8 of 8 cohorts are outlined below in Table 14.

Table 14: Baseline Demographic and Clinical Characteristics: 7 of 8 and 8 of 8 Cohort Treated Analysis Population in Study GVHD-1
7 of 8 Cohort	8 of 8 Cohort
ORENCIA (+ CNI and MTX) N=43	ORENCIA (+ CNI and MTX) N=73	Placebo (+CNI and MTX) N=69
Age - Median	38	44	40
Age - Range	6-76	6-71	7-74
Gender - Male	27 (63)	41 (56)	37 (54)
White	31 (72)	63 (86)	61 (88)
Black or African American	7 (16)	3 (4.1)	2 (2.9)
Asian	2 (4.7)	4 (6)	2 (2.9)
Hispanic	7 (16)	4 (6)	2 (2.9)
Malignancy type
Acute Myeloid Leukemia (AML)	15 (35)	30 (41)	22 (32)
Myelodysplastic Syndrome (MDS)	11 (26)	15 (21)	12 (17)
Acute Lymphoblastic Leukemia (ALL)	8 (19)	20 (27)	22 (32)
Acute leukemia or ambiguous lineage	1 (2.3)	0	1 (1.4)
Hodgkin and Non-Hodgkin lymphoma	1 (2.3)	1 (1.4)	1 (1.4)
Acute Lymphoblastic Lymphoma in 2nd or Greater Complete Remission	1 (2.3)	4 (6)	1 (1.4)
Chronic Myelomonocytic leukemia	1 (2.3)	1 (1.4)	4 (6)
Chronic Myelogenous leukemia	4 (9)	1 (1.4)	5 (7)
Not reported	1 (2.3)	1 (1.4)	1 (1.4)
GVHD Prophylaxis
Cyclosporine	16 (37)	11 (15)	11 (16)
Tacrolimus	27 (63)	62 (85)	58 (84)
Type of Graft
Bone Marrow	21 (49)	33 (45)	26 (38)
Cytokine Mobilized Peripheral Blood (PBSC)	22 (51)	40 (55)	43 (62)
Conditioning Regimen
TBI and Chemotherapy	11 (26)	20 (27)	26 (38)
Busulfan and Cyclophosphamide	13 (30)	28 (38)	21 (30)
Busulfan and Fludarabine	8 (19)	7 (10)	2 (2.9)
Melphalan and Fludarabine	11 (26)	18 (25)	20 (29)

Efficacy was established based on overall survival (OS) and grade II-IV aGVHD free survival (GFS) results assessed at Day 180 post-transplantation. ORENCIA + CNI and MTX did not significantly improve grade III-IV GFS versus placebo + CNI and MTX at Day 180 post-transplantation. The efficacy results of the GVHD-1 8 of 8 cohort are shown in Table 15.

Table 15: Efficacy Results in 8 of 8 Cohort in Study GVHD-1 at Day 180 Post-Transplantation
^aGr III-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade III-IV aGVHD, or death by any cause up to Day 180 post-transplantation. ^bGr II-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade II-IV aGVHD, or death by any cause up to Day 180 post-transplantation.
Endpoint	ORENCIA (+CNI and MTX) n=73	Placebo (+CNI and MTX) n=69
Gr III-IV aGVHD Free Survival ^aRate (95% CI)	87% (77%, 93%)	75% (63%, 84%)
Hazard Ratio (95% CI)	0.55 (0.26, 1.18)
Gr II-IV aGVHD Free Survival ^bRate (95% CI)	50% (38%, 61%)	32% (21%, 43%)
Hazard Ratio (95% CI)	0.54 (0.35, 0.83)
Overall Survival Rate (95% CI)	97% (89%, 99%)	84% (73%, 91%)
Hazard Ratio (95% CI)	0.33 (0.12, 0.93)

In an exploratory analysis of the 7 of 8 cohort of ORENCIA-treated patients (n=43), the rates of Grade III-IV GVHD-free survival, Grade II-IV GVHD-free survival, and overall survival at day 180 post-transplantation were 95% (95% CI 83%, 99%), 53% (95% CI 38%, 67%), and 98% (95% CI 85%, 100%), respectively.

Study GVHD-2

GVHD-2 (NCT05421299) was a clinical study that used data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study analyzed outcomes of ORENCIA in combination with a CNI and MTX, versus a CNI and MTX alone, for the prophylaxis of aGVHD, in patients 6 years of age or older who underwent HSCT from a 1 allele-mismatched URD between 2011 and 2018. The ORENCIA + CNI and MTX-treated group (n=54) included 42 patients from GVHD-1, in addition to 12 patients treated with ORENCIA 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 from patients who had not received ORENCIA during the study period. Analyses used propensity score matching and inverse probability of treatment weighting to help address the impact of selection bias.

Efficacy was based on Overall Survival (OS) at Day 180 post-HSCT. The OS rate at Day 180 in the ORENCIA in combination with CNI and MTX group was 98% (95% CI: 78, 100) and the OS rate at Day 180 in the CNI and MTX group was 75% (95% CI: 67, 82).

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