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Soliris

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Soliris

Soliris

CLINICAL PHARMACOLOGY

Mechanism of Action

Eculizumab, the active ingredient in Soliris, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Soliris inhibits terminal complement mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

A genetic mutation in patients with PNH leads to the generation of populations of abnormal RBCs (known as PNH cells) that are deficient in terminal complement inhibitors, rendering PNH RBCs sensitive to persistent terminal complement-mediated destruction. The destruction and loss of these PNH cells (intravascular hemolysis) results in low RBC counts (anemia), and also fatigue, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots.

In aHUS, impairment in the regulation of complement activity leads to uncontrolled terminal complement activation, resulting in platelet activation, endothelial cell damage and thrombotic microangiopathy.

Pharmacodynamics

In the PNH placebo-controlled clinical study, Soliris when administered as recommended reduced hemolysis as shown by the reduction of serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L). In the single arm clinical study, Soliris maintained this effect through 52 weeks [see Clinical Studies].

Pharmacokinetics

A population PK analysis with a standard 1-compartmental model was conducted on the multiple dose PK data from 40 PNH patients receiving the recommended Soliris regimen [see DOSAGE AND ADMINISTRATION]. In this model, the clearance of Soliris for a typical PNH patient weighing 70 kg was 22 mL/hr and the volume of distribution was 7.7 L. The half-life was 272 ± 82 hrs (mean ± SD). The mean observed peak and trough serum concentrations of Soliris by week 26 were 194 ± 76 mcg/mL and 97 ± 60 mcg/mL, respectively.

A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 57 aHUS patients receiving the recommended Soliris regimen in studies 1, 2 and 3. In this model, the clearance of Soliris for a typical aHUS patient weighing 70 kg was 14.6 mL/hr and the volume of distribution was 6.14 L. The elimination half-life was 291 h (approximately 12.1 days).

The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange increased the clearance of eculizumab to 3660 mL/hr and reduced the half-life to 1.26 hours. Supplemental dosing is recommended when Soliris is administered to aHUS patients receiving plasma infusion or exchange [see Recommended Dosage Regimen].

Dedicated studies have not been conducted to evaluate the PK of Soliris in special patient populations identified by gender, race, age (pediatric or geriatric), or the presence of renal or hepatic impairment. Pediatric and adolescent patients (less than 18 years of age) and patients with renal impairment were included in the aHUS clinical studies [see Clinical Studies]. Population PK analysis showed age, gender, race, and renal function do not influence the PK of eculizumab.

Clinical Studies

PNH

The safety and efficacy of Soliris in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (Study 1); PNH patients were also treated with Soliris in a single arm 52 week study (Study 2); and in a long term extension study. Patients received meningococcal vaccination prior to receipt of Soliris. In all studies, the dose of Soliris was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Soliris was administered as an intravenous infusion over 25 - 45 minutes.

Study 1

PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either Soliris (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the “set-point”) which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications.

Major baseline characteristics were balanced (see Table 7).

Table 7: PNH Study 1 Patient Baseline Characteristics

Parameter Study 1
Placebo
N = 44
Soliris
N = 43
Mean age (SD) 38 (13) 42 (16)
Gender - female (%) 29 (66) 23 (54)
History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19)
Patients with history of thrombosis (events) 8 (11) 9 (16)
Concomitant anticoagulants (%) 20 (46) 24 (56)
Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33)
Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3)) 17 (14, 25) 18 (12, 24)
Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1)
Pre-treatment LDH levels (median, U/L) 2,234 2,032
Free hemoglobin at baseline (median, mg/dL) 46 41

Patients treated with Soliris had significantly reduced (p < 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 8). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of Soliris treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of Soliris on thrombotic events could not be determined.

Table 8: PNH Study 1 Results

  Placebo
N = 44
Soliris
N = 43
Percentage of patients with stabilized hemoglobin levels 0 49
Packed RBC units transfused per patient (median) 10 0
(range) (2 - 21) (0 - 16)
Transfusion avoidance (%) 0 51
LDH levels at end of study (median, U/L) 2,167 239
Free hemoglobin at end of study (median, mg/dL) 62 5

Study 2 and Extension Study

PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received Soliris over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 Soliris-treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total Soliris exposure time ranging from 10 to 54 months. There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during Soliris therapy was not studied [see WARNINGS AND PRECAUTIONS].

aHUS

Three single-arm studies [(two prospective (aHUS Studies 1 and 2) and one retrospective (aHUS Study 3)] evaluated the safety and efficacy of Soliris for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of Soliris or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of Soliris in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in aHUS Study 3 was based on body weight [see Recommended Dosage Regimen]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints.

Endpoints related to TMA included the following:

  • platelet count change from baseline
  • hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks)
  • complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks)
  • TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of > 25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement)
  • Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day).
aHUS Resistant to PE/PI (aHUS Study 1)

aHUS Study 1 enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤ 150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in aHUS Study 1 had an ADAMTS-13 level above 5%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 9 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 1.

Table 9: Baseline Characteristics of Patients Enrolled in aHUS Study 1

Parameter aHUS Study 1
N = 17
Time from aHUS diagnosis until screening in months, median (min, max) 10 (0.26, 236)
Time from current clinical TMA manifestation until screening in months, median (min, max) < 1 ( < 1, 4)
Baseline platelet count ( 109/L), median (range) 118 (62, 161)
Baseline LDH (U/L), median (range) 269 (134, 634)

Patients in aHUS Study 1 received Soliris for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extension study. In aHUS Study 1, the median duration of Soliris therapy was approximately 38 weeks (range: 2 weeks to 64 weeks).

Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of Soliris. Soliris reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS Study 1, mean platelet count increased from 109 ± 32 x109/L at baseline to 169 ± 72 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count at week 26: 210 ± 68 x109/L). Table 10 summarizes the efficacy results for aHUS Study 1.

Table 10: Efficacy Results for aHUS Study 1 in PE/PI-Resistant aHUS

Efficacy Parameter aHUS Study 1
N=17
Change in platelet count from baseline through week 26 (x 109/L), least square mean (95% CI)1 73 (40-105)
Hematologic normalization2, n (%) 13 (76)
Median Duration of hematologic normalization, weeks (range)2 37 (25, 62)
Complete TMA response, n (%) 11 (65)
Median Duration of complete TMA response, weeks (range)2 38 (25, 56)
TMA event-free status, n (%) 15 (88)
Daily TMA intervention rate, median (range)  
  Before eculizumab 0.88 (0.04, 1.59)
  On eculizumab treatment 0 (0, 0.31)
Change in eGFR (mL/min/1.73 m²) at 26 weeks, median (range) +20 (-1, 98)
eGFR improvement ≥ 15 mL/min/1.73 m², n (%)2 9 (53)
Median duration of eGFR improvement, days (range)2 251 (70-392)
1 Calculated at each post-dose day of measurement (excluding Days 1 to 4) through Week 26 using a repeated measurement ANOVA model.
2 At data cut-off (September 8, 2010).

Renal function, as measured by median eGFR, was improved during Soliris therapy. Four of the five patients who required dialysis at study entry were able to discontinue dialysis for the duration of Soliris treatment, and one patient developed a new dialysis requirement.

In aHUS Study 1, responses to Soliris were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins.

aHUS Sensitive to PE/PI (aHUS Study 2)

aHUS Study 2 enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first Soliris dose. Patients on chronic dialysis were permitted to enroll in aHUS Study 2. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in aHUS Study 2 had an ADAMTS-13 level above 5%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 11 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 2.

Table 11: Baseline Characteristics of Patients Enrolled in aHUS Study 2

Parameter aHUS Study 2
N=20
Time from aHUS diagnosis until screening in months, median (min, max) 48 (0.66, 286)
Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45)
Baseline platelet count ( 109/L), median (range) 218 (105, 421)
Baseline LDH (U/L), median (range) 200 (151, 391)

Patients in aHUS Study 2 received Soliris for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extension study. In aHUS Study 2, the median duration of Soliris therapy was approximately 40 weeks (range: 26 to 52 weeks). Table 12 summarizes the efficacy results for aHUS Study 2.

Table 12: Efficacy Results for aHUS Study 2 in PE/PI-Sensitive aHUS

Efficacy Parameter aHUS Study 2
N=20
TMA Event-free status n (%) (95% CI)1 16 (80) (56 - 94)
Daily TMA intervention rate, median (range)  
  Before eculizumab 0.23 (0.05, 1.09)
  On eculizumab treatment 0
Change in platelet count from baseline through week 26 (x 109/L), least square mean (95% CI)1 5 (-17.5 - 28)
   
Hematologic normalization2, n (%) 18 (90)
Median duration of hematologic normalization, weeks (range)3 38 (22, 52)
Complete TMA response, n (%) 5 (25)
Median duration of complete TMA response, weeks (range)3 32 (12, 38)
Change in eGFR (mL/min/1.73 m²) at 26 weeks, median (range) +5 (-1, 20)
eGFR improvement ≥ 15 mL/min/1.73 m², n (%) 1 (5)
1 Calculated at each post-dose day of measurement (excluding Days 1 to 4) through Week 26 using a repeated measurement ANOVA model.
2 In aHUS Study 2, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI.
3 At data cut-off (October 10, 2010).

In aHUS Study 2, responses to Soliris were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Reduction in terminal complement activity was observed in all patients after commencement of Soliris. Soliris reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count was 229 ± 78 x109/L at baseline, and 233 ± 69 x109/L at week 26. Renal function, as measured by median eGFR, was maintained during Soliris therapy. No patient required new dialysis with Soliris.

Retrospective Study in Patients with aHUS (aHUS Study 3)

The efficacy results for the aHUS retrospective study (aHUS Study 3) were generally consistent with results of the two prospective studies. Soliris reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count increased from 171 ± 83 x109/L at baseline to 233 ±109 x109/L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count at week 26: 254 ± 79 x109/L).

A total of 19 pediatric patients (ages 2 months to 17 years) received Soliris in aHUS Study 3. The median duration of Soliris therapy was 16 weeks (range 4 to 70 weeks) for children < 2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to < 12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to 17 years of age (n=4). Fifty three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody.

Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in aHUS Studies 1 and 2 (Table 13). No pediatric patient required new dialysis during treatment with Soliris.

Table 13: Efficacy Results in Pediatric Patients Enrolled in aHUS Study 3

Efficacy Parameter < 2 yrs
(n=5)
2 to < 12 yrs
(n=10)
12 to < 18 yrs
(n=4)
Total
(n=19)
Platelet count normalization, n (%)1 4 (80) 10 (100) 3 (75) 17 (89)
Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42)
Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42)
Daily TMA intervention rate, median (range)
  Before eculizumab 1 (0, 2) < 1 (0.07, 1.46) < 1 (0, 1) 0.31 (0.00, 2.38)
  On eculizumab treatment < 1 (0, < 1) 0 (0, < 1) 0 (0, < 1) 0.00 (0.00 , 0.08)
Patients with eGFR improvement ≥ 15 mL/min/1.73 m², n (%)2 2 (40) 6 (60) 1 (25) 9 (47)
1 Platelet count normalization was defined as a platelet count of at least 150,000 X 109/L on at least two consecutive measurements spanning a period of at least 4 weeks.
2 Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m², one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation.

Last reviewed on RxList: 9/30/2011
This monograph has been modified to include the generic and brand name in many instances.

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