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Pharmacology: Pharmacodynamics: SOLIRIS is a recombinant humanised monoclonal IgG2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. The SOLIRIS antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. SOLIRIS is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.
SOLIRIS is produced in a murine myeloma (NS0 cell line) expression system and purified by affinity and ion exchange chromatography. The bulk drug substance manufacturing process also includes specific viral inactivation and removal steps.
Mechanism of Action: Eculizumab, the active ingredient in SOLIRIS, is a terminal complement inhibitor 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. Eculizumab preserves the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.
In patients with PNH, uncontrolled terminal complement activation and the resulting complement-mediated intravascular haemolysis are blocked with SOLIRIS treatment.
In most patients with PNH, eculizumab serum concentrations of approximately 35 μg/ml are sufficient for essentially complete inhibition of terminal complement-mediated intravascular haemolysis.
In PNH, chronic administration of SOLIRIS resulted in a rapid and sustained reduction in complement-mediated haemolytic activity.
In patients with aHUS, uncontrolled terminal complement activation and the resulting complement-mediated TMA are blocked with SOLIRIS treatment.
All patients treated with SOLIRIS when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In all patients with aHUS, eculizumab serum concentrations of approximately 50 to 100 μg/ml are sufficient for essentially complete inhibition of terminal complement activity.
In aHUS, chronic administration of SOLIRIS resulted in a rapid and sustained reduction in complement-mediated TMA.
In patients with refractory gMG, uncontrolled terminal complement activation causes membrane attack complex (MAC) dependent lysis and C5a-dependent inflammation at the neuromuscular junction (NMJ) leading to failure of neuromuscular transmission. Chronic administration of SOLIRIS results in immediate, complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥116 μg/mL).
In patients with NMOSD, uncontrolled terminal complement activation caused by autoantibodies against AQP4 leads to the formation of the MAC and C5a-dependent inflammation which results in astrocyte necrosis and increased permeability of the blood brain barrier, as well as death of the surrounding oligodendrocytes and neurons. Chronic administration of SOLIRIS results in immediate, complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥116 μg/mL).
Clinical efficacy and safety: Paroxysmal Nocturnal Haemoglobinuria (PNH): The safety and efficacy of SOLIRIS in patients with PNH with haemolysis were assessed in a randomized, double-blind, placebo-controlled 26-week study (C04-001). Patients with PNH were also treated with SOLIRIS in a single group 52-week study (C04-002); and in a long-term extension study (E05-001). Patients received meningococcal vaccination prior to receipt of SOLIRIS. In all studies, the dose of eculizumab was 600 mg 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. Eculizumab was administered as an IV infusion over 25 to 45 minutes. An observational non-interventional Registry in patients with PNH (M07-001) was also initiated to characterize the natural history of PNH in untreated patients and the clinical outcomes during SOLIRIS treatment.
In study C04-001, patients with PNH with at least 4 transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100000/μL 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 haemoglobin concentration (the "set-point") which would define each patient's haemoglobin stabilization and transfusion outcomes. The haemoglobin 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. Primary efficacy endpoints were haemoglobin stabilization (patients who maintained a haemoglobin concentration above the haemoglobin set-point and avoid any RBC transfusion for the entire 26 week period) and blood transfusion requirement. Fatigue and health-related quality of life (QoL) were relevant secondary endpoints. Haemolysis 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 1).
In the non-controlled study C04-002, patients with PNH with at least 1 transfusion in the prior 24 months and at least 30000 platelets/μL 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. Baseline characteristics are shown in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageIn Study C04-001, patients treated with SOLIRIS had significantly reduced (p < 0.001) haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 2). These effects were seen among patients within each of the 3 pre-study RBC transfusion strata (4 to 14 units; 15 to 25 units; >25 units). After 3 weeks of SOLIRIS treatment, patients reported less fatigue and improved health-related QoL. Because of the study sample size and duration, the effects of SOLIRIS on thrombotic events could not be determined. In Study C04-002, 96 of the 97 enrolled patients completed the study (1 patient died following a thrombotic event). A reduction in intravascular haemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in increased transfusion avoidance, a reduced need for RBC transfusion and less fatigue (see Table 2).
Click on icon to see table/diagram/imageFrom the 195 patients that originated in Studies C04-001 and C04-002 and other initial studies, SOLIRIS-treated patients with PNH were enrolled in a long-term extension study (E05-001). All patients sustained a reduction in intravascular haemolysis 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, this finding was shown in non-controlled clinical studies.
The PNH registry (M07-001) was used to evaluate the efficacy of SOLIRIS in patients with PNH with no history of RBC transfusion. These patients had high disease activity as defined by elevated haemolysis (LDH ≥1.5 × ULN [upper limit of normal]) and the presence of related clinical symptom(s): fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin <100 g/L), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction.
In the PNH Registry, patients treated with SOLIRIS were observed to have a reduction in haemolysis and associated symptoms. At 6 months, patients treated with SOLIRIS with no history of RBC transfusion had significantly (p < 0.001) reduced LDH levels (median LDH of 305 U/L; Table 3). Furthermore, 74% of the patients treated with SOLIRIS experienced clinically meaningful improvements in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score (i.e., increase by 4 points or more) and 84% in European Organization for Research and Treatment of Cancer (EORTC) fatigue score (i.e., decrease by 10 points or more). (See Table 3.)
Click on icon to see table/diagram/imageAtypical Haemolytic Uraemic Syndrome (aHUS): Data from 100 patients in 4 prospective controlled studies, 3 in adult and adolescent patients (C08-002A/B C08-003A/B, C10-004) 1 in paediatric and adolescent patients (C10-003), and 30 patients in 1 retrospective study (C09-001r) were used to evaluate the efficacy of SOLIRIS in the treatment of aHUS.
Study C08-002A/B was a prospective, controlled, open-label study which accrued patients in the early phase of aHUS with evidence of clinical TMA manifestations with platelet count ≤150 × 109/L despite PE/PI, and LDH and serum creatinine above ULN.
Study C08-003A/B was a prospective, single arm, open-label study which accrued patients with longer term aHUS without apparent evidence of clinical TMA manifestations and receiving chronic PE/PI (≥1 PE/PI treatment every 2 weeks and no more than 3 PE/PI treatments/week for at least 8 weeks before the first dose). Patients in both prospective studies were treated with SOLIRIS for 26 weeks and most patients enrolled into a long-term, open-label extension study. All patients enrolled in both prospective studies had an ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) level above 5%.
Patients received meningococcal vaccination prior to receipt of SOLIRIS or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of SOLIRIS in adult and adolescent patients with aHUS 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 for the study duration. SOLIRIS was administered as an IV infusion over 35 minutes. The dosage regimen in paediatric patients and adolescents weighing less than 40 kg was defined based on a PK simulation that identified the recommended dose and schedule based on body weight (see Dosage & Administration).
Primary endpoints included platelet count change from baseline in Study C08-002A/B and TMA event-free status in Study C08-003A/B. Additional endpoints included TMA intervention rate, haematologic normalization, complete TMA response, changes in LDH, renal function and QoL. TMA-event free status was defined as the absence for at least 12 weeks of the following: decrease in platelet count of > 25% from baseline, PE/PI, and new dialysis. TMA interventions were defined as PE/PI or new dialysis. Haematologic normalization was defined as normalization of platelet counts and LDH levels sustained for ≥ 2 consecutive measurements for ≥ 4 weeks. Complete TMA response was defined as haematologic normalization and a ≥ 25% reduction in serum creatinine sustained in ≥ 2 consecutive measurements for ≥ 4 weeks. Baseline characteristics are shown in Table 4. (See Table 4.)
Click on icon to see table/diagram/imagePatients in aHUS Study C08-002A/B 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 C08-002A/B, the median duration of SOLIRIS therapy was approximately 100 weeks (range: 2 weeks to 145 weeks).
A reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of SOLIRIS. Reduction in terminal complement activity was observed in all patients after commencement of SOLIRIS. Table 5 summarizes the efficacy results for aHUS Study C08-002A/B. All rates of efficacy endpoints improved or were maintained through 2 years of treatment. Complete TMA response was maintained by all responders. When treatment was continued for more than 26 weeks, 2 additional patients achieved and maintained complete TMA response due to normalization of LDH (1 patient) and a decrease in serum creatinine (2 patients).
Renal function, as measured by estimated glomerular filtration rate (eGFR), was improved and maintained during SOLIRIS treatment. Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis for the duration of SOLIRIS treatment, and 1 patient developed a new dialysis requirement. Patients reported improved health-related QoL.
In aHUS Study C08-002A/B, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins.
Patients in aHUS Study C08-003A/B 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 C08-003A/B, the median duration of SOLIRIS therapy was approximately 114 weeks (range: 26 to 129 weeks). Table 5 summarizes the efficacy results for aHUS Study C08-003A/B.
In aHUS Study C08-003A/B, 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. All rates of efficacy endpoints improved or were maintained through 2 years of treatment. Complete TMA response was maintained by all responders. When treatment was continued for more than 26 weeks, 6 additional patients achieved and maintained Complete TMA response due to a decrease in serum creatinine. No patients required new dialysis with SOLIRIS. Renal function, as measured by median eGFR, increased during SOLIRIS therapy. (See Table 5.)
Click on icon to see table/diagram/imageaHUS Study C10-004 enrolled 41 patients who displayed signs of TMA. In order to qualify for enrolment, patients were required to have a platelet count below the lower limit of normal (LLN) range, evidence of haemolysis such as an elevation in serum LDH, and serum creatinine above the ULN, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in aHUS Study C10-004 had an ADAMTS13 level above 5%. An identified complement regulatory factor mutation or auto-antibody was reported in 51% of patients. A total of 35 patients received PE/PI prior to SOLIRIS treatment. Table 6 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study C10-004. (See Table 6.)
Click on icon to see table/diagram/imagePatients in aHUS Study C10-004 received SOLIRIS for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients elected to continue on chronic dosing.
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 C10-004, mean (± SD) platelet count increased from 119 ± 66 × 109/L at baseline to 200 ± 84 × 109/L by 1 week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 252 ± 70 × 109/L). Renal function, as measured by eGFR, was improved during SOLIRIS therapy. Twenty of the 24 patients who required dialysis at baseline were able to discontinue dialysis during SOLIRIS treatment. Table 7 summarizes the efficacy results for aHUS study C10-004. (See Table 7.)
Click on icon to see table/diagram/imageLonger term treatment with SOLIRIS (median 52 weeks ranging from 15 to 126 weeks) was associated with an increased rate of clinically meaningful improvements in adult patients with aHUS. When SOLIRIS treatment was continued for more than 26 weeks, three additional patients (63% of patients in total) achieved complete TMA response and four additional patients (98% of patients in total) achieved haematologic normalization. At the last evaluation, 25 of 41 (61%) patients achieved eGFR improvement of ≥ 15 ml/min/1.73 m2 from baseline.
Generalized Myasthenia Gravis (gMG): Data from 139 patients in 2 prospective controlled studies (Studies C08-001 and ECU-MG-301) and 1 open-label extension study (ECU-MG-302) were used to evaluate the efficacy of SOLIRIS in the treatment of patients with refractory gMG.
Study ECU-MG-301 was a 26-week double-blind, randomized, placebo-controlled, multicenter Phase 3 study of SOLIRIS in patients who had failed previous therapies and remained symptomatic. A total of 118 (94%) of the 125 patients completed the 26-week Treatment Period and 117 (94%) patients subsequently enrolled in Study ECU-MG-302, an open-label, multicenter long-term safety and efficacy extension study during which all patients received SOLIRIS treatment.
In Study ECU-MG-301, patients with refractory gMG with a positive serologic test for anti-acetylcholine receptor (AchR) antibodies, Myasthenia Gravis Foundation of America (MGFA) clinical classification Class II to IV and Myasthenia Gravis Activities of Daily Living profile (MG-ADL, a patient reported outcome measure validated in gMG) total score ≥ 6 were randomized to either SOLIRIS (N = 62) or placebo (N = 63). All patients included in the study were patients with refractory gMG who met the following predefined criteria: Failed treatment for at least 1 year with 2 or more immunosuppressant therapies (ISTs), either in combination or as monotherapy, ie, patients continued to have impairment in ADL despite ISTs; OR Failed at least 1 IST and required chronic PE or IVIg to control symptoms, ie, patients require PE or IVIg on a regular basis for the management of muscle weakness at least every 3 months over previous 12 months.
Patients received meningococcal vaccination prior to initiating treatment with SOLIRIS or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In Studies ECU-MG-301 and ECU-MG-302, the dose of SOLIRIS in adult patients with refractory gMG was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg at Week 5 ± 2 days, then 1200 mg every 14 ± 2 days for the study duration. SOLIRIS was administered as an IV infusion over 35 minutes.
Table 8 presents the baseline characteristics of patients with refractory gMG enrolled in Study ECU-MG-301. (See Table 8.)
Click on icon to see table/diagram/imageThe primary endpoint for Study ECU-MG-301 was the change from baseline in MG-ADL total score at Week 26. The primary analysis of the MG-ADL was a worst-rank ANCOVA (analysis of covariance) with a mean rank of 56.6 for SOLIRIS and 68.3 for placebo, based on 125 patients (p = 0.0698).
The key secondary endpoint was the change from baseline in the Quantitative MG Score for disease severity (QMG - a validated clinician-reported assessment of muscle weakness in gMG) total score at Week 26. The primary analysis of the QMG was a worst-rank ANCOVA with a mean rank of 54.7 for SOLIRIS and 70.7 for placebo, based on 125 patients (p = 0.0129).
Efficacy outcomes for prespecified repeated measures analyses of the primary and secondary endpoints are provided in Table 9. (See Table 9.)
Click on icon to see table/diagram/imageIn Study ECU-MG-301, a clinical responder in the MG-ADL total score was defined as having at least a 3-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was 59.7% on SOLIRIS compared with 39.7% on placebo (p = 0.0229).
In Study ECU-MG-301, a clinical responder in the QMG total score was defined as having at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was 45.2% on SOLIRIS compared with 19% on placebo (p = 0.0018).
Available data suggest that clinical response is usually achieved by 12 weeks of SOLIRIS treatment.
Table 10 presents an overview of the patients reporting clinical deterioration and patients requiring rescue therapy during 26 weeks of treatment. (See Table 10.)
Click on icon to see table/diagram/imageOf the 125 patients enrolled in Study ECU-MG-301, 117 patients subsequently enrolled in a long-term extension (Study ECU-MG-302), during which all patients received SOLIRIS.
The long-term efficacy of SOLIRIS in patients with refractory gMG as measured by the improvement or maintenance of all measures (MG-ADL, QMG, Myasthenia Gravis Composite [MGC], and Myasthenia Gravis Quality of Life 15-item scale [MG-QoL15]) was demonstrated. For patients who received SOLIRIS in Study ECU-MG-301 (SOLIRIS/SOLIRIS group of Study ECU-MG-302), improvements were sustained for more than 130 weeks of additional treatment with SOLIRIS in Study ECU-MG-302. For patients who received placebo in Study ECU-MG-301 (placebo/SOLIRIS group of Study ECU-MG-302), improvement occurred rapidly after initiating treatment with SOLIRIS and was maintained for more than 130 weeks in Study ECU-MG-302. This treatment effect was observed consistently across both patient- and Treating Physician-assessed measures, using disease-specific and non-disease-specific measurements. Figure 1 presents the change from Baseline in both MG-ADL (panel A) and QMG (panel B) after 26 weeks of treatment in Study ECU-MG-301 and after 130 weeks of treatment in Study ECU-MG-302. (See Figure 1.)
Click on icon to see table/diagram/imageTwenty-two (17.6%) elderly patients with refractory gMG (> 65 years of age) were treated with SOLIRIS in Studies ECU-MG-301 and ECU-MG-302. No substantial differences were seen in safety and efficacy related to age.
Neuromyelitis Optica Spectrum Disorder (NMOSD): Data from 143 patients in 1 controlled study (Study ECU-NMO-301) and 119 patients who continued in 1 open-label extension study (Study ECU-NMO-302) were used to evaluate the efficacy and safety of SOLIRIS in the treatment of patients with NMOSD. The primary objective of this clinical development program was to assess SOLIRIS treatment effect on the prevention of relapses in these patients.
Study ECU-NMO-301 was a double-blind, randomized, placebo-controlled, multicenter, Phase 3 study of SOLIRIS in patients with NMOSD. A total of 124 (86.7%) patients completed the study. A total of 119 (83.2%) patients subsequently enrolled in Study ECU-NMO-302, an open-label, multicenter, long-term safety and efficacy extension study in which all patients receive SOLIRIS treatment.
In Study ECU-NMO-301, patients with NMOSD with a positive serologic test for anti-AQP4 antibodies, a 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, and an Expanded Disability Status Scale (EDSS) score ≤ 7 were randomized 2:1 to either SOLIRIS (N = 96) or placebo (N = 47).
Patients were permitted to receive background IST at stable dose during the study, with the exclusion of rituximab and mitoxantrone.
Patients received either meningococcal vaccination at least 2 weeks prior to initiating treatment with SOLIRIS or prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In the SOLIRIS NMOSD clinical development program, the dose of SOLIRIS in adult patients with NMOSD was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg at Week 5 ± 2 days, then 1200 mg every 14 ± 2 days for the study duration. SOLIRIS was administered as an IV infusion over 35 minutes.
Overall, the demographic characteristics of patients were similar in the 2 treatment groups. Consistent with the NMOSD population, the majority (90.9%) of patients were female. Approximately half were White (49.0%). The median age at first dose of SOLIRIS was 45 years. Disease history and baseline characteristics are presented in Table 11. (See Table 11.)
Click on icon to see table/diagram/imageThe primary endpoint for Study ECU-NMO-301 was the time to first On-trial Relapse as adjudicated by an independent committee who were blinded to treatment. A significant effect on the time to first adjudicated On-trial Relapse was observed for SOLIRIS compared with placebo (p < 0.0001) (Figure 2). The hazard ratio (95% confidence interval [CI]) for eculizumab compared with placebo was 0.058 (0.017, 0.197), representing a 94.2% reduction in the risk of relapse. At ~1 year (48 weeks), 97.9% of SOLIRIS-treated patients were relapse free (versus 63.2% in placebo-treated patients). This effect was sustained through ~3 years (144 weeks), at which point 96.4% of SOLIRIS-treated patients remained relapse free (versus 45.4% in placebo-treated patients). A significant effect on the time to first adjudicated On-trial Relapse was observed for SOLIRIS compared with placebo across most IST subgroups (baseline corticosteroids alone, baseline azathioprine, baseline mycophenolate mofetil), including the subgroup with no ISTs at baseline. In 34 (23.8%) patients with no ISTs at baseline, which includes both patients never on ISTs and patients who previously took ISTs for relapse prevention, a significant effect on the time to first adjudicated On-trial Relapse was observed in patients treated with SOLIRIS monotherapy compared with patients treated with placebo (p < 0.0001). (See Figure 2.)
Click on icon to see table/diagram/imageThe adjudicated On-trial Annualized Relapse Rate (ARR) ratio (95% CI) for SOLIRIS compared with placebo was 0.045 (0.013, 0.151), representing a 95.5% relative reduction in adjudicated On-trial ARR for patients treated with SOLIRIS compared with placebo (p < 0.0001) (see Table 12).
Click on icon to see table/diagram/imageAs compared with placebo, SOLIRIS treatment reduced annualized rates of both On-trial Relapse-associated hospitalization (0.04 vs 0.31 for placebo, p < 0.0001) and acute relapse treatment (IV methylprednisolone: 0.07 vs 0.42 for placebo, p < 0.0001; PE: 0.02 vs 0.19 for placebo, p = 0.0001).
The distribution of changes from Baseline to end of study on other secondary endpoints favored SOLIRIS treatment over placebo across all neurologic disability (EDSS score [p = 0.0597] and modified Ranking Scale [mRS; nominal p = 0.0154]), functional disability (Hauser Ambulation Index [HAI; nominal p = 0.0002]) and QoL (EQ-5D [European Quality of Life Health 5-item Questionnaire] VAS [visual analog scale; nominal p = 0.0309] and EQ-5D Index [nominal p = 0.0077]) measures (see Table 13).
Click on icon to see table/diagram/imageThe final analysis of Study ECU-NMO-302 demonstrates a statistically significant and clinically meaningful reduction in On-trial ARR (as determined by the Treating Physician) on SOLIRIS treatment, based on the median (minimum, maximum) change (-1.825 [-6.38, 1.02], p < 0.0001) from the historical ARR (24 months prior to screening in Study ECU-NMO-301). Results from the final analysis continue to support those of Study ECU-NMO-301.
Integrated data from Studies ECU-NMO-301 and ECU-NMO-302 show that an estimated 93.9% of patients treated with SOLIRIS remained relapse free (based on adjudicated On-trial Relapses) at Week 192.
SOLIRIS has not been studied for the treatment of acute relapses in patients with NMOSD.
Paediatric Population: Paroxysmal Nocturnal Haemoglobinuria: A total of 7 paediatric patients with PNH, with a median weight of 57.2 kg (range of 48.6 to 69.8 kg) and aged from 11 to 17 years (median age: 15.6 years), received SOLIRIS in study M07-005.
Treatment with SOLIRIS at the proposed dosage regimen in the paediatric population was associated with a reduction of intravascular haemolysis as measured by serum LDH level. It also resulted in a marked decrease or elimination of blood transfusions, and a trend towards an overall improvement in general function. The efficacy of SOLIRIS treatment in paediatric patients with PNH appears to be consistent with that observed in adult patients with PNH enrolled in PNH pivotal Studies (C04-001 and C04-002) (Tables 2 and 14). (See Table 14.)
Click on icon to see table/diagram/imageAtypical Haemolytic Uremic Syndrome: A total of 15 paediatric patients (ages 2 months to 12 years) received SOLIRIS in aHUS Study C09-001r. Forty seven percent of patients had an identified complement regulatory factor mutation or auto-antibody. The median time from aHUS diagnosis to first dose of SOLIRIS was 14 months (range < 1 to 110 months). The median time from current TMA manifestation to first dose of SOLIRIS was 1 month (range < 1 to 16 months). The median duration of SOLIRIS therapy was 16 weeks (range 4 to 70 weeks) for children under 2 years of age (N = 5) and 31 weeks (range 19 to 63 weeks) for children 2 years to less than 12 years of age (N = 10).
Overall, the efficacy results of these paediatric patients appeared consistent with what was observed in patients enrolled in aHUS pivotal Studies C08-002 and C08-003 (Table 5). No paediatric patient required new dialysis during treatment with SOLIRIS. (See Table 15.)
Click on icon to see table/diagram/imageIn paediatric patients with shorter duration of current severe clinical TMA manifestation prior to eculizumab, there was TMA control and improvement of renal function with eculizumab treatment (Table 15).
In paediatric patients with longer duration of current severe clinical TMA manifestation prior to eculizumab, there was TMA control with eculizumab treatment. However, renal function was not changed due to prior irreversible kidney damage (see Table 16).
Click on icon to see table/diagram/imageA total of 22 paediatric and adolescents patients (aged 5 months to 17 years) received SOLIRIS in aHUS Study C10-003.
In Study C10-003, patients who enrolled in the study were required to have a platelet count < lower limit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH above the upper limits of normal and serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 years (range: 5 months to 17 years). Patients enrolled in aHUS C10-003 had an ADAMTS-13 level above 5%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 17 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study C10-003. (See Table 17.)
Click on icon to see table/diagram/imagePatients in aHUS C10-003 received SOLIRIS for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients elected to continue on chronic dosing. 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. The mean (±SD [standard deviation]) platelet count increased from 88 ± 42 × 109/L at baseline to 281 ± 123 × 109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 × 109/L). Renal function, as measured by eGFR, was improved during SOLIRIS therapy. Nine of the 11 patients who required dialysis at baseline no longer required dialysis after Study Day 15 of eculizumab treatment. Responses were similar across all ages from 5 months to 17 years of age. In aHUS Study C10-003, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 18 summarizes the efficacy results for aHUS Study C10-003. (See Table 18.)
Click on icon to see table/diagram/imageLonger term treatment with SOLIRIS (median 55 weeks ranging from 1 day to 107 weeks) was associated with an increased rate of clinically meaningful improvements in paediatric and adolescent patients with aHUS. When SOLIRIS treatment was continued for more than 26 weeks, one additional patient (68% of patients in total) achieved Complete TMA Response and 2 additional patients (91% of patients in total) achieved haematologic normalization. At the last evaluation, 19 of 22 patients (86%) achieved eGFR improvement of ≥ 15 ml/min/1.73 m2 from baseline. No patient required new dialysis with SOLIRIS.
Pharmacokinetics: Pharmacokinetics and Drug Metabolism: Biotransformation: Human antibodies undergo endocytotic digestion in the cells of the reticuloendothelial system. Eculizumab contains only naturally occurring amino acids and has no known active metabolites. Human antibodies are predominately catabolized by lysosomal enzymes to small peptides and amino acids.
Elimination: No specific studies have been performed to evaluate the hepatic, renal, lung, or gastrointestinal routes of excretion/elimination for SOLIRIS. In normal kidneys, antibodies are not excreted and are excluded from filtration by their size.
Pharmacokinetic Parameters: In 40 patients with PNH, a 1-compartmental model was used to estimate pharmacokinetic parameters after multiple doses. Mean clearance was 0.31 ± 0.12 ml/hr/kg, mean volume of distribution was 110.3 ± 17.9 ml/kg, and mean elimination half-life was 11.3 ± 3.4 days. Based on these data, the onset of steady state is predicted to be approximately 49 to 56 days.
In patients with PNH, PD activity correlates directly with eculizumab serum concentrations and maintenance of trough levels above ≥35 μg/ml results in essentially complete blockade of haemolytic activity in the majority of patients with PNH.
A second population-PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 37 patients with aHUS receiving the recommended SOLIRIS regimen in studies C08-002A/B and C08-003A/B. In this model, the clearance of SOLIRIS for a typical patient with aHUS weighing 70 kg was 0.0139 L/hr and the volume of distribution was 5.6 L. The elimination half-life was 297 h (approximately 12.4 days).
The second population-PK model was applied to the multiple dose PK data from 22 paediatric patients with aHUS receiving the recommended SOLIRIS regimen in aHUS C10-003. The clearance and volume of distribution of SOLIRIS are weight dependent, which forms the basis for a weight categorical based dose regimen in paediatric patients (see Dosage & Administration). Clearance values of SOLIRIS in paediatric patients with aHUS were 10.4, 5.3, and 2.2 ml/hr with body weight of 70, 30, and 10 kg, respectively; and the corresponding volume of distribution values were 5.23, 2.76, and 1.21 L, respectively. The corresponding elimination half-life remained almost unchanged within a range of 349 to 378 h (approximately 14.5 to 15.8 days).
The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange resulted in an approximately 50% decline in eculizumab concentrations following a 1-hour intervention and the elimination half-life of eculizumab was reduced to 1.3 hours. Supplemental dosing is recommended when SOLIRIS is administered to patients with aHUS receiving plasma infusion or exchange (see Dosage & Administration).
All patients with aHUS treated with SOLIRIS when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In patients with aHUS, PD activity correlates directly with eculizumab serum concentrations and maintenance of trough levels of approximately 50-100 μg/ml result in essentially complete blockade of terminal complement activity in all patients with aHUS.
PK parameters are consistent across PNH, aHUS, refractory gMG, and NMOSD patient populations.
PD activity measured by free C5 concentrations of < 0.5 ug/mL, is correlated with essentially complete blockade of terminal complement activity in patients with PNH, aHUS, refractory gMG, and NMOSD.
Special Populations: Dedicated studies have not been conducted to evaluate the PK of eculizumab in special patient populations identified by sex, race, age (geriatric), or presence of renal or hepatic impairment. Population-PK analysis on data collected across studies in patients with PNH, aHUS, refractory gMG, and NMOSD showed that sex, race, age (geriatric), or presence of renal or hepatic impairment do not influence the PK of eculizumab. Body weight was a significant covariate resulting in a lower eculizumab clearance in paediatric patients requiring body weight-based dosage in paediatric patients.
Paediatric population: The PK of eculizumab was evaluated in Study M07-005 in paediatric patients with PNH (aged from 11 to less than 18 years), and in Studies C08-002, C08-003, C09-001r and C10-003 in paediatric patients with aHUS (aged 2 months to less than 18 years) with body weight-based dosage regimen.
Weight was a significant covariate resulting in a lower eculizumab clearance 0.0105 L/h in the adolescent patients with PNH. Dosing for paediatric patients <40 kg is based on paediatric patients with aHUS.
Toxicology: Preclinical safety data: The specificity of eculizumab for C5 in human serum was evaluated in two in vitro studies.
The tissue cross-reactivity of eculizumab was evaluated by assessing binding to a panel of 38 human tissues. C5 expression in the human tissue panel examined in this study is consistent with published reports of C5 expression, as C5 has been reported in smooth muscle, striated muscle, and renal proximal tubular epithelium. No unexpected tissue cross-reactivity was observed.
Animal reproduction studies have not been conducted with eculizumab due to lack of pharmacologic activity in non-human species.
In a 26-week toxicity study performed in mice with a surrogate antibody directed against murine C5, treatment did not affect any of the toxicity parameters examined. Haemolytic activity during the course of the study was effectively blocked in both female and male mice.
No clear treatment-related effects or adverse effects were observed in reproductive toxicology studies in mice with a surrogate terminal complement inhibitory antibody, which was utilized to assess the reproductive safety of C5 blockade. These studies included assessment of fertility and early embryonic development, developmental toxicity, and pre- and post-natal development.
When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (approximately 4 times the maximum recommended human SOLIRIS dose, based on a body weight comparison); however, the exposure did not increase foetal loss or neonatal death.
No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential of eculizumab or its effect on fertility.
