Summary Basis of Decision for Soliris ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
SolirisTM
Eculizumab, 10 mg/mL, Solution, Intravenous
Alexion Pharmaceuticals, Inc.
Submission control no: 122467
Date issued: 2009-07-22
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02322285
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On January 28, 2009, Health Canada issued a Notice of Compliance to Alexion Pharmaceuticals, Inc. for the drug product, Soliris.
Soliris contains the medicinal ingredient eculizumab, which is a recombinant humanized IgG2/G4 antibody.
Soliris is indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria (PNH) to reduce haemolysis. Patients suffering from PNH are deficient in the expression of terminal complement inhibitors, particularly on red blood cells (RBCs). This results in intravascular haemolysis and other severe and life-threatening symptoms including anaemia, fatigue, pain, haemoglobinuria, renal failure, and thrombosis. Eculizumab is believed to inhibit the complement-mediated lysis of RBCs deficient in terminal complement inhibitors.
The market authorization was based on submitted data from quality (chemistry and manufacturing), non-clinical, and clinical studies. Clinical efficacy and safety were assessed in patients with PNH with a history of at least one transfusion during the past two years, in the multicenter studies: TRIUMPH, a placebo-controlled study; and in interim results from the two open-label trials: SHEPHERD, and E05-001, a long-term, extension study. Clinical evidence from TRIUMPH demonstrated that treatment with Soliris provided statistically significant improvements relative to the placebo in both primary endpoints: haemoglobin stabilization and the number of units of packed RBCs transfused. Interim results from the SHEPHERD study also showed statistically significant reductions in haemolysis as was measured by serum lactate dehydrogenase (LDH) area under the curve (AUC) changes from baseline. Patients with PNH who were enrolled in the pivotal studies (TRIUMPH and SHEPHERD), and in non-pivotal PNH studies were enrolled in E05-001, the long term extension study. The most commonly reported adverse events in the two pivotal trials in patients treated with Soliris were headache (44.2-52.6%), nasopharyngitis (23.3-32.0%), upper respiratory tract infection (14.0-29.9%), and nausea (16.3-20.6%). There were clinically and statistically significantly fewer thromboembolic events (TEs) with Soliris treatment than during the same time prior to treatment.
Soliris (eculizumab) is supplied as a 10 mg/mL solution in 30-mL single-use vials. Therapy consists of the administration of a 600 mg intravenous dose of Soliris 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. Dosing guidelines are available in the Product Monograph.
Soliris is contraindicated for patients with unresolved, serious infections including Neisseria meningitidis, and patients must be currently vaccinated against meningitidis. Patients treated with Soliris have an increased susceptibility to serious infection with encapsulated organisms. Vaccination may not prevent all meningococcal infections and patients should be educated and closely monitored in order to promptly detect and treat infection. Soliris should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Soliris are described in the Product Monograph.
Priority Review status was granted for the evaluation of Soliris as it appeared to provide promising evidence that the drug has the potential to provide effective treatment of a serious, life-threatening, severely debilitating disease for which no drug is presently marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Soliris is favourable for the treatment of patients with PNH to reduce haemolysis.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Eculizumab, the medicinal ingredient of Soliris, is a recombinant humanized monoclonal IgG2/G4 antibody that binds to the human C5 (hC5) complement protein and inhibits the activation of terminal complement, a component of the immune system. PNH is a very rare acquired genetic disorder. Patients with PNH have an acquired mutation of blood stem cells that results in a deficiency of terminal complement inhibitors normally present on the cell surface. This deficiency renders RBCs, and in some patients, their platelets and white blood cells, vulnerable to complement-mediated destruction resulting in haemolysis and other severe and life-threatening symptoms including: anaemia, fatigue, pain, haemoglobinuria, renal failure, and blood clots. Eculizumab is believed to inhibit the complement-mediated lysis of RBCs deficient in terminal complement inhibitors by binding to the hC5. This action prevents the generation of the terminal complement complex C5b-9, in turn reducing the destruction of cells, thereby preventing intravascular haemolysis and improving the symptoms of the disease.
Manufacturing Process and Process Controls
Eculizumab is manufactured using a 5000-L scale, fed-batch mammalian cell culture process. The purification process consists of a combination of chromatography and viral inactivation/removal steps. Process validation data demonstrate that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The drug substance manufacturing process has been scaled-up and optimized during development. The process changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release and characterization data have also been used to support the comparability assessment.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that eculizumab consistently exhibits the desired characteristic structure and biological activity.
Comparability of eculizumab lots produced by different processes was performed and comparable physicochemical characteristics were demonstrated.
Control of Drug Substance
The drug substance specifications and analytical methods used for the quality control of eculizumab are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The impurities that were reported and characterized were found to be within acceptable limits.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The proposed packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life, storage conditions, and shipping conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Soliris drug product is a sterile, clear, colourless, preservative-free, 10 mg/mL solution for intravenous (IV) infusion. The product is formulated at pH 7.0. Each 30-mL single-use vial of Soliris contains 300.0 mg of eculizumab, 13.8 mg sodium phosphate monobasic, 53.4 mg sodium phosphate dibasic, 263.1 mg sodium chloride, 6.6 mg polysorbate 80 (vegetable origin), and water for injection.
Soliris is filled into 30-mL United States Pharmacopeia/European Pharmacopoeia (USP/Ph. Eur.) Type 1 borosilicate glass vials with a target fill volume of 31.7 mL to allow for complete withdrawal of the labelled contents. The vials are stoppered with siliconized rubber stoppers and sealed with aluminum seals with polypropylene flip-off caps.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of eculizumab with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Soliris, rationale for choice of the formulation, the manufacturing process including packaging, and information on batches used in in vitro studies for characterization. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The Soliris drug product manufacturing process consists of pooling formulated bulk from the individual bulk containers, making up a drug substance batch, and filling into 30-mL vials.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Soliris is tested to verify that its identity, appearance, assay, pH, particle size, fill volume, particulates, sterility, moisture content, protein content, osmolality, colour, clarity, levels of degradation products, drug-related impurities, foreign particulate matter, bacterial endotoxins, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within acceptable limits and/or were qualified from batch analysis and, therefore, are considered to be acceptable.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 30-month shelf-life at 2-8°C for Soliris, protected from light, is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
An On-Site Evaluation of facilities involved in the manufacture and testing of Soliris has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
The design, operations, and controls of the facility and equipment that are involved in the production of Soliris are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Steps from the purification process designed to remove and inactivate viruses are adequately validated.
The results for the testing of non-viral adventitious agents are acceptable. Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Soliris has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The murine anti-hC5 antibody N19/8 recognizes hC5 and can effectively block its cleavage into C5a and C5b, thereby blocking terminal complement activation. In order to develop an anti-hC5 antibody, a panel of mouse hybridomas specific for hC5 were generated. The antibodies that they produced were evaluated for their ability to block complement-mediated haemolysis and C5a generation. to a level equal or superior to that of the reference monoclonal antibody (mAb), N19/8. Pharmacodynamic (PD) studies demonstrated that the anti-hC5 mAb m5G1.1 is a potent complement inhibitor, consistently demonstrating comparable or better haemolytic blocking activity and C5a inhibition than N19/8. Consequently, m5G1.1 was selected for further development.
Given that the human immune system recognizes murine antibodies as foreign, a humanized version of m5G1.1 was developed in order to reduce immunogenicity. This process involved minimizing the murine components of m5G1.1 in such a way that the specificity and affinity of the original antibody was not lost. The humanization process consisted of grafting the complementarity determining regions (CDRs) of the antibody into human antibody frameworks. The affinity or specificity of the antibody was not compromised following the humanization process. The humanized version of the antibody was chosen for further development as its overall sequence was more similar to human antibody sequences. It was designated as h5G1.1 (eculizumab).
A complement-mediated haemolytic assay was conducted to investigate whether eculizumab exhibits species cross-reactivity. As expected, eculizumab effectively blocked haemolytic activity of human serum with complete inhibition demonstrated at approximately 100 nM of antibody. However, eculizumab did not effectively block haemolytic activity of the sera of any other primate or non-primate species tested, even at extremely high concentrations of antibody.
An in vitro tissue cross-reactivity study was conducted using various samples of cryopreserved human tissues. In order to detect the binding ability of eculizumab in normal human tissues, the antibody was applied to cryosections (3 donors per tissue, where available) at two concentrations, 5 µg/mL and 30 µg/mL. C5-specific staining was observed in smooth and striated (skeletal) muscle in various tissues and was expressed in multiple cell types including myoepithelium, myofibroblasts, renal tubular epithelium, and reticulum cells. The C5-expression patterns observed are consistent with published reports.
In summary, the results of the PD studies suggest that eculizumab is highly specific for hC5 and is capable of effectively blocking the cleavage of C5 into C5a and C5b, thereby blocking terminal complement activation. The findings of the PD studies supported the further development of eculizumab as a potentially effective therapeutic for the restoration of terminal complement inhibition in PNH patients.
3.2.2 Pharmacokinetics
Eculizumab does not recognize C5 from any species other than humans, therefore, traditional non-clinical pharmacokinetic (PK) studies could not be conducted. However, C5-deficient mice reconstituted with physiologically relevant serum levels of hC5 were used as a model for the direct evaluation of antibody plasma clearance and complement inhibition in vivo.
Pharmacokinetic analyses were performed to measure the serum concentrations of h5G1.1 G4 mAb (an eculizumab variant) following IV or subcutaneous (SC) administration of a 50 µg dose of the antibody. Following IV injection, a relatively rapid T1/2α of several hours was followed by a slow decline in serum concentrations over the next 48 hours. In contrast, SC administration was followed by a progressive rise in serum concentration such that serum levels of the antibody at 24 hours and thereafter were comparable to those measured following IV injection.
Although h5G1.1 G4 mAb is a humanized antibody and its PK effect in mice is not predictive of that in humans, the C5-deficient mouse model does allow for the determination of the molar ratio of antibody to hC5 required to inhibit complement-dependent serum haemolytic activity in vitro. The concentration of h5G1.1 G4 mAb and hC5 in each serum sample was measured and then used to calculate the molar ratios of antibody to hC5 at various time points. Based on the measured hC5 and h5G1.1 G4 mAb serum concentrations, it was determined that h5G1.1 G4 mAb completely blocked hC5-dependent haemolysis at a molar ratio of approximately 0.5 to 1.0 (h5G1.1 G4 mAb to hC5). This is consistent with the fact that mAbs have two antigen-binding sites and therefore theoretically bind antigen at a ratio of 0.5 moles of antibody to 1.0 moles of antigen. Furthermore, based upon the average hC5 plasma concentration of 75 µg/mL, and a plasma volume of 3.0 L for a 70 kg human, it was predicted that a single dose of 1.5 to 2.0 mg/kg of h5G1.1 G4 mAb should be sufficient to acutely mediate complete inhibition of complement-dependent serum haemolytic activity in vivo in humans.
The PK study results indicated that h5G1.1 G4 mAb, an eculizumab variant, was able to efficiently inhibit hC5-dependent complement activity in vivo in the mammalian model system. Following IV administration of h5G1.1 G4 mAb in mice, a rapid and potent dose-dependent inhibition of hC5-dependent serum haemolytic activity was observed at doses ≥50 µg. Inhibition of haemolytic activity was maintained for at least 48 hours following single administration. Subcutaneous administration also provided protection from hC5-dependent serum haemolytic activity for at least 48 hours, although there was an initial 12 to 24 hour delay in this effect.
3.2.3 Toxicology
Eculizumab has been shown to be specific for hC5. No other species exhibit a pharmacologically active response to eculizumab, therefore, toxicity testing was conducted in CD-1 mice utilizing BB5.1 mAb, a surrogate murine anti-mouse C5 antibody.
Single-Dose Toxicity
Single-dose toxicity studies were not performed with eculizumab or any other surrogate anti-C5 antibody.
Repeat-Dose Toxicity
The dose level and dosing frequency used in the toxicity studies were selected to efficiently inhibit C5-dependent complement activity resulting in sufficient haemolytic inhibition. The single dose level of 30 mg/kg of body weight (bw) was utilized in all studies at frequencies of once or twice weekly. These doses represent approximately 2 to 4 times, and 4 to 8 times the recommended human dose, respectively. In addition, the 4-week study included dosing at 30 mg/kg bw, three times weekly.
Sub-chronic testing in CD-1 mice was carried out for 4 weeks and 26 weeks. The treatment was well-tolerated and there were no clinical signs of toxicosis observed in any of the treated groups in either study.
Genotoxicity and Carcinogenicity
Genotoxicity and carcinogenicity studies were not conducted as they are generally not considered to be applicable to biotechnology-derived pharmaceuticals. In general, antibodies do not interact directly with deoxyribonucleic acid (DNA), therefore, it is unlikely that they have genotoxic potential.
Reproductive and Developmental Toxicity
In reproductive toxicity studies, maximal inhibition of haemolysis was not attained in the majority of the treated animals. The reason for this is unknown. There were no treatment-related effects observed on male or female fertility, embryo-foetal toxicity, nor on maternal function.
The developmental and perinatal/postnatal studies indicated that there was the potential for developmental effects at all treatment levels, in the absence of maternal toxicity. Hence, it is recommended that pregnant women not be treated with eculizumab unless the potential benefit justifies the potential risk to the mother and foetus. In addition, breast-feeding should be discouraged in lactating women receiving treatment with eculizumab.
Immunotoxicity
Immunotoxicity testing was not conducted, therefore, the potential for the increased risk of infections while undergoing treatment must be considered.
3.2.4 Summary and Conclusion
The non-clinical PD and PK data provided support for the mechanism of action of eculizumab to block complement-mediated haemolysis and C5a generation. In addition, the data contributed to the establishment of a suggested dose sufficient to acutely mediate complete inhibition of complement-dependent serum haemolytic activity in vivo in humans for the treatment of PNH.
Furthermore, the non-clinical toxicology database was considered adequate to assess the safety profile of eculizumab and support its use in humans, provided that adequate safety precautions are taken, as described above.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The PD activity of Soliris was measured with an in vitro serum complement haemolysis assay to estimate the extent of terminal complement inhibition in the serum of patients. Administration of Soliris resulted in a rapid and sustained reduction in terminal complement activity.
On the basis of biochemical studies, it was estimated that patients should maintain a serum trough level ≥35 µg/mL Soliris for effective therapeutic effect. In practice, however, the dosing regimen and amounts employed in the pivotal clinical trials (and stated in the Product Monograph) typically produced a serum level three times this effective value at steady-state, and a level almost five times this value immediately after infusion. This is to ensure that the level of eculizumab (Soliris) in the serum can meet and maintain the required target (trough levels approximately 35 µg/mL) to fully inhibit the terminal complement-mediated intravascular haemolysis in most PNH patients.
The dosage regimen consists of the administration of 600 mg of Soliris per week for the first 4 weeks. A further 900 mg of Soliris is administered in the fifth week, followed by a 900 mg maintenance dose every other week thereafter. In clinical trials, this dosage regimen resulted in a rapid and sustained reduction in haemolytic activity. This routine was found to completely block haemolysis within 60 minutes; however, the simulated serum profile under these circumstances predicts serum fluctuations and steady-state values far in excess of the effective concentration (35 µg/mL). There is no known increased incidence of adverse events (AEs) resulting from the administration of this drug every two weeks for prolonged periods of time. Given the dosage regimen and linkage with a target trough concentration, the safety profile of Soliris should be monitored in the post-market environment.
3.3.2 Pharmacokinetics
Soliris exhibits a PK profile that has been described using a one compartmental model, as an approximation to the complex disposition, with a mean elimination half-life of approximately 11.3 days (271 hours), and a central volume of distribution (110.3 mL/kg) thought to be primarily limited to the vascular space. The mode of administration is by IV infusion over a 30-minute period, with a predicted time to reach steady-state of 46 to 56 days with the dosage regimen noted.
Clinical studies to examine the specific pathways for the excretion of Soliris have not been conducted. However, due to its molecular size (148 kD), eculizumab, like other immunoglobulins, is not eliminated by normal renal filtration.
No clinical studies have been conducted in special patient populations to determine the effects of age, race, gender, or metabolic status (renal or hepatic impairment) on the PK of Soliris. The consolidated PK/PD model predicted no significant differences in eculizumab disposition based on age, race, or gender.
Similar to endogenous immunoglobulins, Soliris consists of naturally occurring L-amino-acids and is not subject to metabolic transformation by cytochrome P450 (CYP) enzymes. As a result, no differences in Soliris pharmacokinetics are expected due to tobacco use, concomitant medications metabolized by CYP enzymes, genetic polymorphisms, or food intake, all of which are factors that can influence CYP processes; however, these factors have not been specifically studied in clinical trials.
3.3.3 Clinical Efficacy
Efficacy data was derived from 184 patients who took part in the following two pivotal studies:
- TRIUMPH - A Haemoglobin Stabilization and Transfusion Reduction Efficacy and Safety Clinical Investigation using Soliris in PNH patients
- SHEPHERD - Safety in Haemolytic PNH Patients treated with Soliris
TRIUMPH was a placebo-controlled, Phase III, randomized, multicentre, double-blind, 26-week study that enrolled 87 PNH patients, 43 who received Soliris and 44 who received placebo. All patients were between the ages of 18-85 years of age with a mean age of 39.7 years. Primary inclusion criteria included:
- At least 4 transfusions in the prior 12 months for anaemia and anaemia-related symptoms;
- Flow cytometric confirmation of ≥10% PNH red blood cells;
- Patients who were taking erythropoietin, Coumadin/heparin, iron supplements, folic acid or immunosuppressants/corticosteroids at baseline had to be on stable doses of various durations depending on the drug(s) being taken;
- A documented lactate dehydrogenase (LDH) level ≥1.5 x the upper limit of normal;
- Platelets ≥100 000/µL;
- Vaccinated against N. meningitides.
Patients were excluded if they had a mean haemoglobin (Hb) level (prior to transfusion) over the previous year >10.5 g/dL or if they had a history of, presence of, or suspicion of, an active bacterial infection at the beginning of the 6-month treatment phase, or recurrent bacterial infections. Other exclusion criteria were listed. Patients who discontinued treatment after being treated with Soliris were to be monitored closely following discontinuation for signs of potentially life-threatening haemolytic events.
Prior to randomization, all patients underwent an initial observation period to confirm the requirement for RBC transfusion and to identify the Hb concentration (the "set-point") which would define each patient's Hb stabilization and transfusion outcomes. The Hb set-point was ≤9 g/dL in patients with symptoms of anaemia and ≤7 g/dL in patients without symptoms.
Patients received 600 mg Soliris or placebo every 7 days for the first 4 weeks, followed by 900 mg 7 days later in week 5, then 900 mg every 14 days thereafter. The co-primary endpoints for the study were Hb stabilization (patients who maintained an Hb concentration above the Hb set-point and avoided any RBC transfusion for the entire 26-week period) and the number of units of packed red blood cells (PRBCs) transfused. Secondary endpoints included: an analysis of transfusion avoidance; the reduction of haemolysis as measured by LDH area under the curve (AUC); and analysis of quality of life (QoL) as measured by changes in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale.
Results from TRIUMPH revealed that Soliris demonstrated statistically significant and clinically relevant improvements relative to placebo in both co-primary endpoints: Hb stabilization and the number of units of PRBCs transfused during the treatment phase of the study. Of the patients treated with Soliris, 49% had stabilized Hb levels at the end of the study, as compared to 0% in the placebo group (p<0.001). There was no statistically significant haemoglobin stabilization in patients who previously required >25 units, although the number of patients in that stratum was small. The median number of units of PRBCs transfused in the 12 months prior to study enrolment were comparable between the two groups: 18 units (range: 7 to 36) for the Soliris group and 17 units (range: 7 to 44) for the placebo group. Soliris patients required statistically significantly (p <0.001) fewer units of PRBCs (0 median, range 0 to 16, 3 mean units per patient) during the 6-month treatment phase compared with placebo patients (10 median, range 2 to 21, 11 mean units per patient). A statistically significant (p <0.001) reduction in median units of PRBCs transfused is also demonstrated in each of the 3 strata subgroups defined according to the number of PRBC units transfused within 1 year prior to screening (low stratum: 4 to 14 units, mid stratum: 15 to 25 units, and high stratum: >25 units). However, several patients' treatment transfusion rates remained similar to their baseline transfusion rates.
Patients in the lowest transfusion stratum had the greatest apparent reduction in mean transfusions.
Additionally, patients who received Soliris demonstrated statistically significant improvements in all secondary endpoints: transfusion avoidance, haemolysis reduction as measured by LDH AUC, and changes in FACIT-F scale.
SHEPHERD was an open-label, multi-centre, 52-week study with the same dosage regimen as TRIUMPH. A total of 97 patients were included in this study, all of whom received treatment with Soliris. Patients showed statistically significant improvements relative to baseline in the primary surrogate of efficacy, LDH AUC. In addition, statistically significant improvements were demonstrated as compared to baseline for both secondary endpoints: haemolysis as measured by LDH change from baseline and QoL as measured by the FACIT-F instrument.
E05-001 was an open-label extension study of both TRIUMPH and SHEPHERD and included 195 patients. The purpose of this study was to collect long-term data for approximately 2.5 years which included 104 weeks of bi-weekly study-drug treatment followed by 16 weeks of non-treatment. At the time of authorization for Soliris, only interim data from 96 patients was available from this study. The primary objectives of this study were to collect data for the evaluation of health-related QoL and to assess the ability of Soliris to effectively treat the sequelae of PNH, as measured by the number of transfusions and the ability to reach and maintain clinical laboratory parameters. No efficacy analyses were prepared for this interim assessment as there were too few patients with sufficient data to allow for a reliable interpretation.
In all three pivotal studies it was determined that Soliris was well-tolerated. There were no cases of haemolysis upon cessation of Soliris treatment in any study.
In the non-pivotal studies, Soliris was also found to be well-tolerated. Patients treated with Soliris appeared to demonstrate clinical benefit, particularly with regard to reductions in the number of blood transfusions required, intravascular haemolysis, and paroxysm rate.
3.3.4 Clinical Safety
Safety data was assessed in the two pivotal clinical studies and the non-pivotal studies described in section 3.3.3 Clinical Efficacy. Other non-pivotal studies conducted with non-PNH patients were also included with the submission and provided safety data.
In the TRIUMPH study, there were more reported AEs in the Soliris group than in the placebo group. These included more neurologic complaints, particularly headache [44% versus (vs.) 27.9%], gastrointestinal disorders (46.5% vs. 36.4%), backache (18.6% vs. 9.1%), fatigue (9.3% vs. 2.3%) herpes simplex (7% vs. 0), and more vascular AEs (4 events vs. 1).
The three most commonly reported AEs in the Soliris-treated patients in the combined pivotal studies were: headache, nasopharyngitis/upper respiratory tract infection, and nausea. Uncommon AEs included jaundice, anorexia, infusion and allergic reactions, and oedema. The majority were mild to moderate in severity. There were clinically and statistically significantly fewer thromboembolic events with treatment in all studies combined, although, because of the study sample size and duration, the effects of Soliris on thrombotic events could not be determined in TRIUMPH. In the pre-treatment period for all studies combined, there were 39 events (14.33 events per 100 patient years); during Soliris treatment there were 3 events (1.07 events per 100 patient years).
Several patients' treatment transfusion rates remained similar to their baseline transfusion rates. In the Product Monograph, physicians are advised to monitor individual patient response by LDH levels. A response occurs in 86% of patients within 3 to 4 weeks of the initiation of treatment with Soliris.
The single dose rather than the unit dose (in mg/kg) results in the highest serum trough levels in patients in the lowest weight quartile. There is no current safety signal in patients with high serum trough levels and/or low patient weight except a trend of more AEs in the lowest quartile of patients in both genders; however, the results must be interpreted with caution, and physicians are advised to monitor AEs in these patients as with all patients treated with Soliris. The Marketed Health Products Directorate, Health Canada, has been requested to monitor AEs in this population. There is no current safety signal with prolonged exposure to Soliris therapy (>2.5 years).
Infrequent, low titre antibody responses have been detected in Soliris-treated patients across all PNH and non-PNH studies with a frequency (3.4%) similar to that of the placebo (4.8%); the significance of this is not known. No patients have developed neutralizing antibodies following therapy with Soliris and there has been no observed correlation of antibody development to clinical response or AEs.
There is an increased risk of AEs and serious AEs (SAEs) with infections caused by encapsulated organisms such as H. influenza and Pneumococcus, however, only immunization against N. meningitidis was recommended and only N. meningitidis infections were recorded. In PNH clinical studies, two patients experienced serious meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis and septicaemia occurred in one unvaccinated patient. Patients are to be advised that immunisation does not prevent all cases of serious infection and both physicians and patients are to monitor for early signs and symptoms of infection. Increased surveillance, monitoring, and treatment of infections are specified in the Product Monograph, including the prescription of prophylactic antibiotics and the issuance of a "Soliris Patient Safety Card" to patients.
Due to the possibility of patients becoming pregnant while undergoing treatment with Soliris and given the fact that the antibody is expected to cross the placental barrier and be present in breast milk, a statement was added to the Product Monograph stating that Soliris should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.
Discontinuation from Soliris therapy was uncommon. As with all protein products, the administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. Infusion reactions did occur during pivotal trials; however, these reactions did not require discontinuation of Soliris. Soliris therapy increases the number of PNH cells [for example, in TRIUMPH, the proportion of PNH RBCs increased among Soliris-treated patients by a median of 28% from baseline (range from 25% to 69%)]; therefore, patients who discontinue treatment with Soliris may be at an increased risk of serious haemolysis. Any patient who discontinues Soliris should be monitored for at least 8 weeks to detect serious haemolysis and other reactions. Further information can be found in the Monitoring after Discontinuation section of the Product Monograph for Soliris.
The safety and efficacy of Soliris therapy in paediatric patients below the age of 18 have not been established. In addition, the safety and efficacy of Soliris therapy in geriatric patients over the age of 65 have also not been established.
3.3.5 Additional Issues
The following post-market commitments should be addressed:
- Submit follow-up safety and efficacy data from all on-going and future trials of Soliris in PNH patients.
- Follow the pharmacovigilance plan to monitor efficacy and safety including:
- Serious infections, infectious agents and subsequent treatment for all patients treated with Soliris
- Advise the Marketed Health Products Directorate of the safety signal identification for AEs and adverse drug reactions (ADRs) in patients with low weight/high serum trough levels of Soliris.
- Create and monitor a registry of Canadian patients with PNH treated with Soliris.
- Submit Periodic Safety Update Reports (PSURs) annually for at least two years. Include in each PSUR an analysis of all ADRs that may be potentially related to the safety profile of Soliris.
- Submit any international commitments regarding the usage of Soliris in PNH patients.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Soliris appears to be highly efficacious in reducing haemolysis as well as the number of required transfusions in the majority of PNH patients who required transfusions. In the Product Monograph, physicians are advised to monitor individual patient response by LDH levels. A response occurs in 86% of patients within 3 to 4 weeks of the initiation of treatment with Soliris.
There were no signals that efficacy or safety was reduced over duration of therapy.
Most patients in the clinical trials experienced mild to moderate AEs, particularly headache (up to 44%), respiratory tract infections, gastrointestinal symptoms and/or fatigue. Few patients discontinued therapy (2.0 to 4.5%). Serious ADRs were rare; however, there were five patients who died in the clinical trials. Of these deaths, four were patients treated with Soliris, each dying of a unique cause: chronic myelomonocytic leukemia, cerebral herniation, complications post-cholecystectomy, and electrocution. In addition, one patient treated with placebo died of pulmonary embolism.
There is an increased risk of AEs and SAEs with infections caused by encapsulated organisms. It is mandatory that patients receiving Soliris be immunized against N. meningitidis. Caution should be used when administering Soliris to patients with any systemic infection. Guidelines for increased surveillance and tracking of infections are described in the Product Monograph.
Based on the review of data on quality, safety and efficacy, the benefit/risk profile of Soliris was found to be favourable for the treatment of patients with PNH to reduce haemolysis.
Priority Review status was granted for the evaluation of Soliris as it appeared to provide promising evidence that the drug has the potential to provide effective treatment of a serious, life-threatening, severely debilitating disease for which no drug is presently marketed in Canada.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Soliris is favourable in the treatment of patients with PNH to reduce haemolysis. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: SolirisTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-12-04 |
| Request for priority status | |
| Filed | 2008-04-18 |
| Approval issued by the Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics | 2008-05-15 |
| Submission filed: | 2008-07-10 |
| Screening | |
| Screening Acceptance Letter issued | 2008-08-01 |
| Review | |
| On-Site Evaluation | 2008-12-03 - 2008-12-05 |
| Quality Evaluation complete | 2009-01-28 |
| Clinical Evaluation complete | 2009-01-28 |
| Biostatistics Evaluation complete | 2009-01-28 |
| Labelling Review complete | 2009-01-23 |
| Notice of Compliance issued by Director General | 2008-01-28 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SOLIRIS | 02322285 | ALEXION PHARMA GMBH | ECULIZUMAB 10 MG / ML |