Soliris (eculizumab)
Company: Alexion Pharm
Approval Status: Approved March 2007
Treatment for: paroxysmal nocturnal hemoglobinuria
Areas: Cardiology/Vascular Diseases; Hematology
| General Information | Clinical Results | Side Effects | Mechanism of Action | Literature References | Additional Information |
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 treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.
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 the drug is 600 mg every 7 days for the first 4 weeks, followed by 900 mg for the fifth dose 7 days later, then 900 mg every 14 days thereafter.
Clinical Results
FDA Approval
FDA approval of Soliris 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% 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 - 45 minutes, at 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 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 - 45 minutes, at 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 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 was not studied.
Ongoing Study Commitments
- Alexion has agreed to evaluate long-term safety of eculizumab
by analyzing outcomes in the Soliris Safety Registry for a time
period of no less than five years. At the end of the five year
period, a study report will be submitted to the Biological License
Application (BLA) that describes the major safety findings from the
registry program, including the specific items listed below and
proposing labeling changes as appropriate. Additionally, annual
interim reports will be submitted to the BLA, along with expedited
reports as specified below. All patients within the registry will
be followed for the occurrence of: (A) Serious infections, defined
as infections necessitating or prolonging hospitalization or
resulting in death. Alexion commits to collecting follow-up
information from these patients to assess the nature of the serious
infection, the duration of hospitalization, the major features of
the clinical course and the survival status. Expedited reporting
(15 day telephone or facsimile Medwatch communication) will be
provided for the occurrence of these serious infections. (B)
Malignancy, including the nature of the malignancy and the survival
status of the patients who develop a malignancy. (C) Use of
eculizumab among pediatric patients under 16 years of age, to
include collection of eculizumab dosage information, as well as the
same information being required for adult patients in the registry.
(D) Pregnancy, including the clinical course of each pregnancy and
the detection of congenital abnormalities among babies born to the
women exposed to eculizumab during the pregnancy. (E) Thrombotic
events, including the nature of the event, the clinical outcome as
well as the antocoagulant management prior to and after the
event.
Protocol Submission: May 2007
Final Report Submission: June 2012 - Alexion has agreed to conduct a randomized, controlled clinical
study to assess the effects of anticoagulant withdrawal among PNH
patients receiving eculizumab. This study will randomize at least
100 anticoagulated patients to either continue or discontinue
anticoagulation therapy. The major outcomes will assess the safety
of discontinuation of anticoagulant therapy while continuing
eculizumab, especially with respect to providing important evidence
regarding major bleeding and that this discontinuation does not
increase the risk for occurrence of thrombotic events in these
patients. A full study report and data from this study will be
submitted to the BLA and may include a label revision, contingent
upon the importance of these study results.
Protocol Submission: June 2007
Study Start June 2009
Final Report Submission: March 2014
Side Effects
Adverse events associated with the use of Soliris may include, but are not limited to, the following:
- Viral Infection
- Headache
- Anemia
- Nasopharyngitis
- Back pain
- Nausea
- Fatigue
- Cough
- Pyrexia
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.
Literature References
Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. The New England Journal of Medicine 2006 Sep 21;355(12):1233-43.
Hill, A Eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Clinical advances in hematology & oncology : H&O 2005 Nov;3(11):849-50.
Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28.
Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. The New England Journal of Medicine 2004 Feb 5;350(6):552-9.
Additional Information
For additional information regarding Soliris or paroxysmal nocturnal hemoglobinuria, please visit the Soliris web page.
The FDA drug information shown here is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.
