Bkemv Drug Information

Paroxysmal Nocturnal Hemoglobinuria (PNH)

The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26-week study (PNH Study 1, NCT00122330); PNH patients were also treated with eculizumab in a single arm 52-week study (PNH Study 2, NCT00122304) and in a long-term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of eculizumab. Eculizumab was administered as an intravenous infusion over 25 - 45 minutes.

PNH 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 eculizumab (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 11 ). Table 11: PNH Patients treated with eculizumab 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 12 ).

After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of eculizumab products on thrombotic events could not be determined. 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. One hundred and eighty-seven eculizumab-treated PNH patients were enrolled in a long-term extension study.

All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab 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 eculizumab products therapy was not studied.

Atypical Hemolytic Uremic

Syndrome (aHUS) Five single-arm studies evaluated the safety and efficacy of eculizumab for the treatment of aHUS. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight. 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 (Study C08-002A/B) Study C08-002A/B 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 × 10 9 /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 Study C08-002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody.

Table 13 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B. Table 13: Baseline Characteristics of Patients Enrolled in Study C08-002A/B 269 Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks).

Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab.

Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08-002A/B, mean platelet count (± SD) increased from /L at baseline to /L by one week; this effect was maintained through 26 weeks /L, and 2 years /L. When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response.

Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 14 summarizes the efficacy results for Study C08-002A/B.

Table 14: Efficacy Results for Study C08-002A/B 0 0 aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B 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 eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08-003A/B.

The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08-003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Table 15: Baseline Characteristics of Patients Enrolled in Study C08-003A/B 200 Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks.

In Study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab.

Platelet counts were maintained at normal levels despite the elimination of PE/PI. Table 16 summarizes the efficacy results for Study C08-003A/B. Mean platelet count (± SD) increased from /L at baseline to /L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week /L).

A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. 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 Studies C08-002A/B and C08-003A/B (Table 17).

No pediatric patient required new dialysis during treatment with eculizumab. Table 17: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r -004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). The median patient age was 35 (range: 18 to 80 years).

All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. A total of 35 patients received PE/PI prior to eculizumab. Table 18 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-004.

Table 18: Baseline Characteristics of Patients Enrolled in Study C -004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment.

In Study C10-004, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 19 summarizes the efficacy results for Study C10-004. Table 19: Efficacy Results for Study C 0 Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥ 97 percentile for age without the need for chronic dialysis.

The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Table 20 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003.

Table 20: Baseline Characteristics of Patients Enrolled in Study C -003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment.

Responses were observed across all ages from 5 months to 17 years of age. Table 21 summarizes the efficacy results for Study C 0 0

Generalized Myasthenia

Gravis (gMG) The efficacy of eculizumab for the treatment of gMG was established in Study ECU-MG-301 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled adult patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score ≥ 6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender, and duration of gMG.

Over 95% of patients in each group were receiving acetylcholinesterase (AChE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen.

The primary efficacy endpoint for Study ECU-MG-301 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24).

A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores. A key secondary endpoint in Study ECU-MG-301 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness.

Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). The results of the analysis of the MG-ADL and QMG from Study ECU-MG-301 are shown in Table 22. Table 22: Analysis of Change from Baseline to Week 26 in In Study ECU-MG-301, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement.

The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥ or 8-point improvement on MG-ADL, and ≥ or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

The efficacy of eculizumab for the treatment of NMOSD was established in NMOSD Study 1 (NCT01892345), a randomized, double-blind, placebo-controlled trial that enrolled 143 patients with NMOSD who were anti-AQP4 antibody positive and met the following criteria at screening: History of at least 2 relapses in last 12 months or 3 relapses in the last 24 months, with at least 1 relapse in the 12 months prior to screening, Expanded Disability Status Scale (EDSS) score ≤7 (consistent with the presence of at least limited ambulation with aid), If on immunosuppressive therapy (IST), on a stable dose regimen, The use of concurrent corticosteroids was limited to 20 mg per day or less, Patients were excluded if they had been treated with rituximab or mitoxantrone within 3 months or with IVIg within 3 weeks prior to screening. A total of 96 patients were randomized to receive eculizumab treatment and 47 were randomized to receive placebo. The baseline demographic and disease characteristics were balanced between treatment groups.

During the treatment phase of the trial, 76% percent of patients received concomitant IST, including chronic corticosteroids; 24% of patients did not receive concomitant IST or chronic corticosteroids during the treatment phase of the trial. The primary endpoint for NMOSD Study 1 was the time to the first adjudicated on-trial relapse. Figure 1: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse – Full Analysis Set Note: Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period.

Abbreviations: CI = confidence interval Eculizumab-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment. Eculizumab-treated patients had a 96% relative reduction in the adjudicated on-trial annualized relapse rate (ARR) compared to patients on placebo, as shown in Table 23. Figure 1