General Information

Soliris is a monoclonal antibody that specifically binds to the complement protein C5, thus inhibiting terminal complement mediated intravascular hemolysis in PNH patients.

Soliris is specifically indicated for the following:

paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis, atypical hemolytic uremic syndrome (AHUS), adults with generalized Myasthenia gravis (gMG) who are antiacetylcholine receptor (AchR) antibody positive and neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

Mechanism of Action

Soliris is a is a recombinant humanized monoclonal IgG2/4 antibody produced by murine myeloma cell culture. A genetic mutation in PNH leads to the generation of abnormal red blood cells (RBCs) that are deficient in terminal complement inhibitors, rendering them sensitive to persistent terminal complement-mediated destruction. The destruction and loss of these RBCs leads to the symptoms associated with PNH. The active ingredient in Soliris, eculizumab, 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.

Side Effects

Adverse events associated with the use of Soliris for PNH may include, but are not limited to, the following:

• viral infection
• headache
• anemia
• nasopharyngitis
• back pain
• nausea
• fatigue
• cough
• pyrexia

Adverse events associated with the use of Soliris for atypical hemolytic uremic syndrome may include, but are not limited to, the following:

• hypertension
• upper respiratory tract infection
• diarrhea
• headache
• anemia
• vomiting
• nausea
• urinary tract infection
• leukopenia

Adverse events associated with the use of Soliris for generalized Myasthenia Gravis may include, but are not limited to, the following:

•  musculoskeletal pain

Adverse effects associated with the use of Soliris for NMOSD may include, but are not limited to, the following:

• upper respiratory infection

• common cold (nasopharyngitis)

• diarrhea

• back pain

• dizziness

• influenza

• joint pain (arthralgia)

• sore throat (pharyngitis)

• contusion

The Soliris drug label comes with the following Black Box Warning: Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.  Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. Immunize patients with meningococcal vaccines at least two weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

Dosing/Administration

Soliris is supplied in 300 mg single-use vials containing 30 mL of 10 mg/mL sterile solution designed for intravenous infusion.

The recommended initial dose of Soliris for PNH is 600 mg every seven days for the first four weeks, followed by 900 mg for the fifth dose seven days later, then 900 mg every 14 days thereafter.

The recommended dose of Soliris for adults 18 years of age and older with AHUS is 900 mg weekly for the first four weeks, followed by 1200 mg for the fifth dose one week later, then 1200 mg every two weeks thereafter. The recommended dose of Soliris for pediatrics under the age of 18 years is based on body weight.

The recommended dose of Soliris for gMG and NMSOD consists of: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every two weeks thereafter. Administer Soliris at the recommended dosage regimen time points, or within two days of these time points.

Clinical Trial Results

The FDA approval of Soliris for PNH was based on the results of three clinical trials.

Study 1
This randomized, double-blind, placebo-controlled trial enrolled 87 subjects who had received at least four transfusions in the prior 12 months, had a flow cytometric confirmation of at least 10 percent PNH cells and platelet counts of at least 100,000/microliter. All subjects received meningococcal vaccination prior to treatment. They were subsequently observed to determine the hemoglobin concentration "set point" in order to define each patient’s hemoglobin stabilization and transfusion outcomes. The subjects were then randomized to receive placebo or Soliris, via intravenous infusion over 25 to 45 minutes, at 600 mg every 7 ± 2 days for four weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for 26 weeks. Primary endpoints included hemoglobin stabilization, the number of RBC units transfused, fatigue and health-related quality of life. Results revealed that the subjects treated with Soliris had significantly reduced hemolysis compared to placebo (p< 0.001), resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions. After 3 weeks of Soliris treatment, patients reported less fatigue and improved health-related quality of life.

Study 2 and extension study
This randomized, double-blind, placebo-controlled trial enrolled 97 subjects, 96 of whom completed treatment, who had received at least one transfusion in the prior 24 months and with at least 30,000 platelets/microliter. All subjects received meningococcal vaccination prior to treatment followed by Soliris, via intravenous infusion over 25 to 45 minutes, at 600 mg every 7 ± 2 days for four weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for 52 weeks. Concomitant medications included anti-thrombotic agents and systemic corticosteroids. The primary endpoints were the same as in study 1. A reduction in intravascular hemolysis, measured by serum LDH levels, was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. The long-term study enrolled 187 Soliris treated subjects. A reduction in intravascular hemolysis over a total Soliris exposure time ranging from 10 to 54 months was sustained by all the subjects. In addition, there were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment. The effects of concomitant anticoagulant therapy withdrawal during Soliris therapy were not studied.

The FDA approval of Soliris for atypical hemolytic uremic syndrome was based on three single-arm studies: two prospective (aHUS studies 1 and 2) and one retrospective study (aHUS study 3). In all studies, the dose of Soliris in adult and adolescent patients was 900 mg every seven days for four weeks, followed by 1200 mg seven days later, then 1200 mg every 14 days thereafter. The dosage regimen for pediatrics weighing less than 40 kg enrolled in aHUS study 3 was based on body weight. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. These endpoints included platelet count change from baseline, hematologic normalization, complete TMA response, TMA-event free status and daily TMA intervention rate.

aHUS Resistant to PE/PI (aHUS Study 1)
This trial enrolled 17 subjects who displayed signs of TMA despite receiving at least four PE/PI treatments the week prior to screening. The subjects received Soliris for a minimum of 26 weeks. Soliris reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count increased from 109 x10(9)/L at baseline to 169 x10(9)/L by one week; this effect was maintained through 26 weeks (mean platelet count at week 26: 210 x10(9)/L). Renal function, as measured by median eGFR, was improved during Soliris therapy. Four of the five subjects who required dialysis at study entry were able to discontinue dialysis for the duration of Soliris treatment.

aHUS Sensitive to PE/PI (aHUS Study 2)
This trial enrolled 20 subjects undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy. The subjects received Soliris for a minimum of 26 weeks. 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 x 10(9)/L at baseline and 233 x10(9)/L at week 26. Renal function, as measured by median eGFR, was maintained during Soliris therapy.

Retrospective Study in Patients with aHUS (aHUS Study 3)
This trial enrolled 19 pediatrics (ages 2 months to 17 years) who received Soliris for a median duration of 16 weeks. 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 x10(9)/L at baseline to 233 x10(9)/L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count at week 26: 254 x10(9)/L). Nine subjects experienced an eGFR improvement of at least 15 mL/min/1.73 m2.

The FDA approval of Soliris for gMG was based on a 26-week randomized, double-blind, parallel-group, placebo-controlled, multicenter trial. A total of 62 patients were randomized to receive Soliris treatment and 63 were randomized to receive placebo. The primary efficacy endpoint for the study 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. A statistically significant difference favoring Soliris was observed in the mean change from baseline to week 26 in MG-ADL total scores (-4.2 points in the Soliris treated group compared with -2.3 points in the placebo-treated group [p=0.006]). 

The FDA approval of Soliris for neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive was based on a study of 143 patients who were randomized to receive either Soliris treatment or placebo. Compared to treatment with placebo, the study showed that treatment with Soliris reduced the number of NMOSD relapses by 94 percent over the 48-week course of the trial. Soliris also reduced the need for hospitalizations and the need for treatment of acute attacks with corticosteroids and plasma exchange.