Mechanism Of Action
ATGAM is composed of antibodies that bind a wide variety
of proteins on the surface of lymphocytes. In addition, ATGAM binds to granulocytes,
platelets, bone marrow cells, and other cell types. The mechanism of
ATGAM-induced immunosuppression has not been determined. Published data
indicate that the primary mechanism is the depletion of circulating
lymphocytes, with greatest effect on T lymphocytes. Lymphocyte depletion may be
caused by complement dependent lysis and/or activation-induced apoptosis. In
addition, immunosuppression may be mediated by the binding of antibodies to
lymphocytes which results in partial activation and induction of T lymphocyte
The mechanism of ATGAM therapy for aplastic anemia is
attributed to its immunosuppressive actions. In addition, ATGAM directly stimulates
the growth of hematopoietic stem cells and release of hematopoietic growth
factors such as interleukin-3 and granulocyte/macrophage colony stimulating
During infusion of 10 to 15 mg/kg/day, the mean peak
value (n = 27 renal transplant patients) was found to be 727 ± 310 μg/mL.
Metabolism And Elimination
The half-life of equine immunoglobulin after ATGAM
infusion was found to be 5.7 ± 3.0 days in one group of recipients. The range
for half-life was 1.5 to 13 days.
Renal Allograft Rejection
Renal Transplant Rejection
The effectiveness of ATGAM for treatment of acute
allograft rejection was evaluated in three different treatment applications: as
a substitute for standard therapy, in conjunction with standard therapy at the
time of diagnosis of the first rejection episode, and in conjunction with standard
therapy in steroid resistant rejection episodes.
A randomized controlled trial of the use of ATGAM as a
substitute for standard therapy for treatment of the first acute rejection
episode was conducted at one transplant center in recipients of living related
renal allografts. A total of 22 patients were studied; 11 in each of the two treatment
groups [ATGAM versus standard therapy (bolus doses of Solu-Medrol®]. Patients randomized to the ATGAM group
received 14–21 doses of ATGAM therapy, starting on the day the rejection was
diagnosed. ATGAM was administered daily according to a dose-byrosette regimen
which resulted in a mean daily dose of approximately 15 mg/kg. Patients
randomized to the control group received Solu- Medrol® at a dosage of 15 mg/kg
starting on the day the rejection was diagnosed, administered either daily or
on alternate days for 3 to 7 doses to complete a maximum total dose of 5,000 mg
for the course of the rejection episode. In this study, ATGAM was at least
effective as standard therapy for treatment of acute allograft rejection. All
11 ATGAM treated patients achieved resolution of first rejection compared with
10/11 control patients. At one year, the functional graft survival rate was 91%
in the ATGAM group (10/11) and 64% in the control group (7/11). Patient
survival was similar in the two treatment groups (11/11 ATGAM patients versus
10/11 control patients).
The effect of ATGAM when administered in conjunction with
standard therapy at the time of diagnosis of the first rejection episode was studied
under two different protocols with cadaveric and living related renal
transplant patients. The results from these studies demonstrate the efficacy
associated with the addition of ATGAM to standard therapy for treatment of the
first rejection episode in renal allograft recipients. In Study 1, a randomized
controlled, two center trial of ATGAM use for treatment of acute rejection in
cadaveric renal transplant patients, the addition of ATGAM to standard
rejection therapy (methylprednisolone sodium succinate) resulted in an
increased frequency of resolution of the first acute rejection episode which
was statistically significant (p < 0.01). ATGAM-treated patients achieved a
rejection resolution rate of 80% (36/45) compared with 54% (25/46) in the
control group. There was a statistically significant improvement in functional
graft survival favoring the ATGAM group (p < 0.01), and a statistically
significant steroid sparing effect during the first rejection episode among
patients in the ATGAM group. There was no difference in the patient survival
rate between the two treatment groups. Study 2 was a randomized controlled
trial conducted at five different transplant centers. In this study, the
addition of ATGAM to standard rejection therapy (bolus doses of Solu-Medrol® for treatment of acute rejection in
recipients of living related renal transplants resulted in an increased
frequency of rejection resolution and improvement in functional graft survival.
Due to the small sample size, the difference between the ATGAM group and the
control group in functional graft survival rate did not achieve statistical
significance. Marginal statistical significance was demonstrated in rejection
reversal rate and intravenous steroid sparing among ATGAM patients (p=0.10 and p=0.07).
Patient survival rates were similar in the two treatment groups.
Results from randomized controlled trials in patients
with first acute renal allograft rejection episodes refractory to conventional
steroid therapy have demonstrated that ATGAM, when administered in conjunction
with standard therapy, yields efficacy results superior to those of standard
therapy alone. One study investigated two different regimens of ATGAM;
immediate and delayed therapy. Patients were enrolled at the time of first
rejection episode and randomized among three treatment groups: control (no
ATGAM), immediate ATGAM, and delayed ATGAM. Patients in all three treatment
groups received standard rejection therapy in the form of bolus doses of
Solu-Medrol®15 mg/kg/day IV, while
patients in the two ATGAM groups received ATGAM therapy in addition to
Solu-Medrol®. In the immediate ATGAM
group, ATGAM administration started at the time of diagnosis of rejection
(concurrent with standard therapy). In the delayed ATGAM group, ATGAM
administration started on rejection day 4 (following the first three doses of
Solu-Medrol®). Patients in both of the treated
groups received from 10 to 21 doses of ATGAM. Results favored the two ATGAM
groups (and particularly the immediate ATGAM group) in both outcome of first
rejection and functional graft survival. The improvement in functional graft
survival was statistically significant (p=0.05). There was also a statistically
significant difference in patient survival rate favoring the ATGAM-treated
The effectiveness of ATGAM for reversal of acute renal
allograft rejection was also demonstrated in other controlled studies performed
in various medical centers. In these studies, ATGAM was administered at time of
diagnosis of the first rejection episode at a range of 10 to 15 mg/kg per day
for 14 to 15 days, followed by alternate day therapy for a total of 21 doses in
The use of ATGAM for the treatment of moderate to severe
aplastic anemia in patients who are unsuitable for bone marrow transplantation is
based on data from three controlled studies.
The effectiveness of the ATGAM therapy in the studies
described below was evaluated by the hematological response and survival rates (Table
10 To 20 mg/kg Daily For 8 To 14 Days
A total of 41 patients with moderate or severe aplastic
anemia ages 6 to 69 years, who were not candidates for bone marrow
transplantation were enrolled in a randomized controlled study. The objective
of this study was to determine the efficacy of ATGAM as a single agent, in restoring
hematopoiesis in patients with moderate to severe aplastic anemia. Twenty-one
(n=21) patients in the ATGAM treatment group received 20 mg/kg/day for 8 days,
while control patients (n=20) were observed for 3 months. All patients were
given oral prednisone (40 mg/m²/day) starting on day 8 then tapered over 1 to 2
At 3 months post-study enrollment, 11 patients in the
supportive care group who showed no improvement became eligible and were
crossed over to receive ATGAM therapy. Efficacy was evaluated as sustained
improvement in peripheral blood counts within 3 months of entry into the study.
A statistically significant (p < 0.01) difference was observed between the two
treatment groups in hematological improvement based on the investigator's
evaluation; 11 of 21 (52%) patients in the ATGAM group responded, compared with
no patients (0 of 20) in the control group. Six of the 11 crossover patients
from the control group showed improvement after 3 months of therapy. Overall,
of 32 patients in both the ATGAM group and the control group who crossed over
to receive ATGAM, 17 patients (53%) had a hematological improvement. Estimated
1-year survival rate was 62% for all 32 patients treated with ATGAM. The 2-year
survival rate was 100% among the ATGAM responders [17 of the 32 patients (53%)
compared to 14% for the nonresponders].
Fever, chills, and erythematous or urticarial rash were
seen in all ATGAM treated patients. Platelet counts decreased during ATGAM infusion
and daily platelet transfusions were necessary. Serum sickness occurred in all
patients within 6 to 18 days of ATGAM initiation and was well-controlled with
standard therapy. Three patients experienced transient hypotension.
A randomized double-blind, placebo prospective,
controlled study was conducted to compare the safety and efficacy of ATGAM and androgen
(oxymetholone; OXY) immunosuppressive therapy with the combination of ATGAM,
androgen (OXY) and an infusion of HLA mismatched bone marrow in patients with
severe aplastic anemia who were not candidates for bone marrow transplantation.
Allocation to treatment group was based on the availability of mismatched bone
marrow donors. A total of 42 patients, ages 1 to 69 years were treated. Eighteen
patients received ATGAM at a dose of 16 mg/kg/day for 10 doses with concomitant
androgens (OXY) at a dose of 3 mg/kg/day for a minimum of 3 months, and 24
patients received an infusion of bone marrow from an HLA-mismatched donor 48
hours after the completion of ATGAM treatment.
At 3 months after entry into the study, 51% of patients
with disease of idiopathic etiology (21 of the 41 evaluable patients from both
groups) showed improvement based on investigator's evaluation of transfusion
requirements and peripheral blood counts. Hematological response rate
(complete/moderate based on sponsor's evaluation) at 3 months for the ATGAM and
androgen group was 44% compared with 43% for the group receiving ATGAM,
androgen and bone marrow infusion. The group of patients who received
mismatched bone marrow infusion had better estimated 1-year survival rate,
although the difference between these estimates was not statistically
significant (p=0.14); 83% at 12 months for the group receiving bone marrow
infusion versus 59% for the ATGAM and androgen alone group. Estimated 1-year
survival rate for both groups combined was 73%.
The most commonly reported adverse events were rash,
fever, arthralgias, chills, headache, myalgia and pruritus.
A pooled analysis of data from Studies 1 and 2 revealed
an overall estimated 1-year survival rate of 69% in ATGAM-treated patients.
A total of 53 patients (3 to 76 years of age)
participated in this randomized, placebo-controlled, double-blind study to
determine if androgens add to the efficacy of ATGAM in providing favorable
hematologic response rates in patients with moderate to severe aplastic anemia.
All patients were treated with ATGAM 20 mg/kg/day IV for 8 days, and were
randomized to receive the oral androgen (oxymetholone 4 mg/kg/day or
fluoxymesterone 25 mg/m²/day) (n=26), or a matched placebo (n=27). Both groups
received oral prednisone (40 mg/m²/day) beginning on Day 8 which was tapered
and discontinued in 1 to 2 weeks. A group of historical controls from previous
studies (n=68; 1 to 72 years of age) who received ATGAM (20 mg/kg/day IV for 8
days) without androgens were included for treatment results comparison. The proportions
of subjects who presented complete or partial response at 6 months were 42% in
the ATGAM plus androgen group, 44% in the ATGAM plus placebo group, and 51% in
the historical controls. The difference in response rates was not significant
(p > 0.9). Survival at 2 years was also comparable in the two groups for
patients with severe aplastic anemia; 55% in the ATGAM plus androgen group
compared with 50% in the ATGAM plus placebo group (p=0.65), and 56% for the
historical controls. In patients with moderate aplastic anemia, twoyear survival
for the ATGAM plus androgen group was 63% compared with 100% in those receiving
ATGAM plus placebo and 72% in the historical controls who received ATGAM alone.
Adverse reactions in both groups were comparable and
included rash, chills, gastrointestinal disturbances, and joint pain during
ATGAM infusion, as well as symptoms of serum sickness in all patients. Five
patients had asymptomatic sinus bradycardia; six patients required antihypertensive
therapy. Alanine transaminase or alkaline phosphatase levels increased to > 2
times the upper limits of normal in 7 patients receiving ATGAM plus androgen,
and in nine patients receiving ATGAM plus placebo.
Table 3: Key Studies with ATGAM for the Treatment of
||ATGAM + comparator or other therapy
||No. of Subjects
||Response rate % (endpoint)*
||Survival rate % (time point)
||P Value (or 95% CI)
|10 to 20 mg/kg/day for 8 to 14 days
||47†/ 52‡(3 mo)
|| < 0.01†/ < 0.01‡
||62§ (12 mo)
||6†/ 0‡(3 mo)
||ATGAM + Bone marrow infusion
||43 (3 mo)
||83 (12 mo)
||44 (3 mo)
||59 (12 mo)
||ATGAM + Androgen
||42 (6 mo)
|| > 0.9
|ATGAM + Placebo
||44 (6 mo)
||50¶ (24 mo)
|ATGAM historical controls
||51 (6 mo)
||56 (24 mo)
|*Hematologic response was defined differently in
†Sponsor's evaluation of response
‡Investigator's evaluation of response
§This survival estimate includes the 21 subjects who were randomized to receive
ATGAM, plus another 11 subjects who were crossed over from the control group.
¶Patients with severe aplastic anemia only.
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