Summary Basis of Decision for Mabcampath ®
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:
Mabcampath®
Alemtuzumab, 10 mg/mL, Solution, Intravenous
Genzyme Corporation
Submission control no: 074429
Date issued: 2007-05-24
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), MABCAMPATH, Alumtuzumab, 10 mg/mL, solution, Genzyme Corporation N° de contrôle de la présentation 074429
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):
- 02273993
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On November 30, 2005, Health Canada issued a Notice of Compliance to Genzyme Corporation for the drug product MabCampath.
MabCampath contains the medicinal ingredient alemtuzumab which is an antineoplastic humanized monoclonal antibody.
MabCampath is indicated for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. The mechanism of action is antibody-dependent lysis of leukemic cells following cell surface binding.
The market authorization was based on submitted data from quality, preclinical, and clinical studies. Efficacy and safety were evaluated in a multi-centre, open-label, non-comparative study of 93 patients with B-CLL who were previously treated with alkylating agents and who had failed treatment with fludarabine; as well as two supportive multi-centre, open-label, non-comparative studies with 56 B-CLL patients who were previously treated with fludarabine or other chemotherapies. Study results demonstrated statistically significant increases in tumour response rates and duration of response in patients treated with MabCampath. However, increased survival or clinical benefits such as improvement in disease-related symptoms have not yet been demonstrated in comparative randomized trials. MabCampath should be administered under the conditions stated in the Product Monograph taking into consideration all potential risks associated with the administration of this drug product.
MabCampath (10 mg/mL alemtuzumab) is presented in ampoules containing 30 mg of alemtuzumab in 3 mL of solution for intravenous use. MabCampath should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Dosing guidelines are available in the Product Monograph.
MabCampath is contraindicated for patients who have active infections, underlying immunodeficiency, known Type I hypersensitivity or anaphylactic reactions to MabCampath or to any one of its components, or active secondary malignancies. Detailed conditions for the use of MabCampath are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of MabCampath is favourable for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (medicinal ingredient)
General Information
Alemtuzumab, the medicinal ingredient of MabCampath, is a recombinant humanized monoclonal antibody that binds to human CD52, a membrane glycoprotein expressed predominantly on peripheral lymphocytes, monocytes, and tissue macrophages. Alemtuzumab causes lysis of these target cells either by the complement pathway or by antibody-dependent cellular cytotoxicity.
Manufacturing Process and Process Controls
Alemtuzumab is produced by recombinant DNA technology in a Chinese Hamster Ovary cell line. The manufacture of alemtuzumab is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants. Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated genetic stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of alemtuzumab comprises a series of steps which include cell culture, harvest, and purification. The purification is performed via a combination of chromatographic and viral inactivation/removal steps. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits and alemtuzumab certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. 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 alemtuzumab consistently exhibits the desired characteristic structure and biological activity. Results from process validation studies also indicate that the methods used during processing adequately control the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of alemtuzumab. The drug substance specifications, and analytical methods used for quality control of alemtuzumab are considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life, storage, and shipping conditions for alemtuzumab are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
The drug product, MabCampath, is a sterile, clear, colourless, isotonic pH 6.8-7.4 solution supplied in single-use clear glass ampoules containing 30 mg of alemtuzumab in 3 mL of solution.
The non-medicinal ingredients are sodium chloride, dibasic sodium phosphate, potassium chloride, potassium dihydrogen phosphate, polysorbate 80, and disodium edetate dihydrate. No preservatives are added. All excipients used in the manufacture of the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
MabCampath is packaged in boxes of three USP Type I glass ampoules.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development were considered acceptable upon review. Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between development and commercial batches.
Manufacturing Process and Process Controls
The drug product is formulated, sterile filtered, and aseptically filled into ampoules using conventional pharmaceutical equipment and facilities.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable.
Control of Drug Product
MabCampath is tested to verify its identity, purity, potency, quantity (protein content), as well as general tests for the physicochemical characteristics of the solution (appearance/colour/clarity, pH, osmolality). Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug product, and to justify the specifications of the drug product. Analytical testing results from final batch analyses were reviewed and considered to be acceptable according to the specifications of the drug product.
Through the lot release testing and evaluation program, consecutively manufactured final product lots were tested, and found to satisfactorily meet the specifications of the drug product.
Stability
Based on the results of the real-time and accelerated stability study data submitted, the proposed 36-month shelf-life at 2-8°C for MabCampath is considered acceptable.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated. Raw materials of animal and recombinant origin used in the production have been 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 Summary and Conclusion
The Chemistry and Manufacturing information submitted for MabCampath 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
Alemtuzumab is a humanized monoclonal antibody with activity against the CD52 antigen that is found predominantly on lymphocytes. A mode of action has not been fully elucidated, however, it is recognized that the oligosaccharides on the CD52 antigen are essential for chronic myelogenous leukemia and antibody-dependent cell-mediated toxicity, but not for binding. The close proximity of the antibody to the cell membrane is likely of relevance, and this relates to the location of the binding site and the small size of the antigen. It has also been postulated that due to the high density of the CD52 antigen on lymphocytes, there is significant Fc-Fc binding between alemtuzumab molecules and Fc binding to cell membrane Fc receptors I & III. The cross-linking of alemtuzumab molecules on the cell surface appears to be an important mechanism for activating other membrane surface molecules which do not interact directly with alemtuzumab.
Extensive studies on normal human tissues were performed to identify cell types that react with the antibody. Apart from major populations of T- and B-lymphocytes, a minor cell population in the skin, as well as mature and maturing spermatozoa were reactive.
The majority of hematopoetic stem cells do not express CD52 although there may be minor populations with CD52 expression. Most B-cell Non-Hodgkin Lymphomas are reactive together with some other lymphomas and leukemias, as well as the typical clonal proliferation in B-CLL. Alemtuzumab has been shown to have an unusually potent lytic effect on CD52 positive lymphocytes.
Drug interaction studies were not submitted.
3.2.2 Pharmacokinetics
The pharmacokinetic studies were conducted in the Cynomolgus monkey. Studies of a humanized monoclonal antibody in another species had significant limitations, most significantly, the development of an anti-alemtuzumab antibody. Alemtuzumab appears to distribute into the blood compartment. Due to the fact that the study period was restricted by the development of anti-alemtuzumab antibodies, it was not possible to determine whether it may also slowly distribute toward a second compartment. Also, the distribution calculations would be affected due to the fact that there is specific antibody binding to the CD52 positive cells.
It is not known whether there were circulating CD52 positive cells/bound alemtuzumab complexes, or whether bound cells were rapidly removed from circulation, although the fall in lymphocyte numbers suggests that bound lymphocytes were promptly removed from circulation. If intravascular lysis occurred, complexes could continue to circulate. The volume of distribution was approximately that of the circulating blood compartment volume.
The initial phase half-life was longer (11.9 and 15.1 hours) in animals receiving a single 3 mg/kg dose, compared to 4.1 and 3.4 hours in the 0.1 & 1.0 mg/kg dosed animals, respectively. It is not clear why the terminal half-life was so long (approximately 220-250 hours) with all doses.
3.2.3 Toxicology
Toxicity studies were performed in Cynomolgus monkeys. These animals were chosen because they have lymphocytes that are CD52 positive that are lysed by alemtuzumab, and the animals are large enough to sustain a schedule of blood sampling.
Studies for carcinogenicity, mutagenicity, or reproductive toxicity were not submitted.
Single-Dose Toxicity
In single-dose studies of 2 mg/kg and 3 mg/kg, (which equate to the proposed human single dose of 3 mg/kg but not to the total dose proposed), there were no toxic events noted but in most cases there was transient neutrophilia. Peripheral blood lymphocytes were decreased. But in the limited number of treatments, no symptoms suggestive of a "first-dose" cytokine release syndrome were seen. During necropsy, there were no abnormal findings. The lack of findings in lymph nodes and other lymphoid tissue was probably due to the small total dose and the interval between dosing and necropsy.
At higher single doses, there was hypotension, as well as increases in urea, lactate dehydrogenase, serum glutamic oxaloacetic transaminase, and hydroxybutyrate dehydrogenase. Anemia may have been drug related or the result of blood sampling. One animal that died after receiving a dose of 30 mg/kg demonstrated laboratory findings which could have been associated with hemolysis, although no hemoglobinuria was reported.
In necropsies, animals that had received sufficient total dose and were necropsied early showed signs of lymphoid tissue involution. In recovered animals, this condition was not seen, suggesting regeneration of lymphoid cells from precursors, although CD markers were not used on the histopathological samples and alterations in lymphocyte subset populations could not be ruled-out.
Multiple-Dose Toxicity
In a multi-dose study, animals received increasing daily doses from 1 mg/kg/day up to 2 mg/kg/day in a 15-day treatment or increasing doses up to 3 mg/kg/day in a 30-day treatment. Apart from the expected lympholyis and histopathologically evident "involution" of lymphoreticular tissues seen in animals necropsied immediately after dosing, there were few findings that were noteworthy.
As seen in other animal studies, the neutrophil counts fluctuated. There was a significant granulocytopenia in the 30-day group in one animal that received both the highest single daily dose regimen (3 mg/kg/day) for the last 16 days of the 30-day dosing period and the highest total dose (67.5 mg/kg). Anemia was seen in all animals, which is likely due to the blood sampling regimen. Non-specific effects included weight-loss and loss of appetite. The maximum proposed human dose is 108 mg over 12 weeks.
Other histological findings reported in test animals were also seen in control animals, although numbers were small. There were no consistent findings, which may suggest a mode of action or toxic side effect unrelated to the interaction of alemtuzumab on lymphocytes.
Animals that received alemtuzumab and necropsied at day 227, showed no particular abnormalities after recovery, with lymphoid tissues appearing normal, although this was only assessed at the level of light microscopy and gross anatomical observation.
Overall, these animal studies identified that when Cynomolgus monkeys were given a dose of 3 mg/kg, the only unexpected events were fluctuations in neutrophil counts, mainly elevated neutrophil counts. Clinically expected reductions of circulating lymphocytes also occurred.
Cardiovascular and Respiratory Toxicity
One study for cardiovascular and respiratory toxicity was carried out on anesthetized Cynomolgus monkeys with three dose regimens: 3 mg/kg, 10 mg/kg and 30 mg/kg. The latter two were above the proposed single-dose level of 3 mg/kg. Increased heart rate and hypotension were consistent findings associated with higher doses. Elevations of urea, lactate dehydrogenase, glutamic oxalaoacetic transaminase, and hydroxybutyrate dehydrogenase were observed in the groups receiving the two highest doses.
The neutrophilia noted in earlier studies was present in all cases. In this study, however, neutrophilia did not occur in animals receiving vehicle control and as such was probably a result of indirect toxicity.
No specific cause of death was given for the one animal that died. The high potassium level associated with a progressive reduction in hemoglobin and red cell count suggests hemolysis, however, no cause for this has been proposed. This effect should therefore be considered as a potential toxic effect of treatment with alemtuzumab.
If the 3 mg/kg dose used in this study is in effect equivalent to the same dose in humans, then the drug and its immediate effects (primarily lympholysis) do not cause significant cardiovascular or respiratory changes.
3.2.4 Summary and Conclusion
Alemtuzumab is an antineoplastic humanized monoclonal antibody with activity against CD52, an antigen present on a wide range of lymphocytes, most monocytes and natural killer cells. Alemtuzumab has been shown to be strongly cytolytic on CD52 positive lymphocytes.
Many tissues were identified as having lymphocytes or macrophages which were, as expected, CD52 positive. Perivascular cuffs of reactive lymphocytes can be seen in several tissues and lymphocytes can occasionally be seen in the skin. The male reproductive tract has been found to express the CD52 antigen. The Product Monograph provides a warning that MabCampath may cause loss of mature sperm, and possibly male infertility. Studies have not been carried out to determine the effect or duration of infertility, if any.
In the peripheral blood, there were a range of cells that were CD52 positive. Over 90% of T-cells and B-cells were CD52 positive. Studies using alemtuzumab as a treatment for a range of hematological malignancies and lymphomas have been carried out and show that all B-CLL and T-CLL leukemias are CD52 positive, and that several other leukemias and related malignancies are also positive in varying percentages.
3.3 Clinical basis for decision
3.3.1 Clinical Program
Three dose-ranging studies included pharmacodynamic (PD) and pharmacokinetic (PK) data, as well as response rates and safety data. Within this group of studies, one was a Phase II, pivotal, open-label, non-comparative study (CAm211) consisting of 93 patients with B-CLL who had previous therapy with an alkylating agent and failure with fludarabine therapy. The study was performed at 22 sites in the US and Europe. Enrolment was 78% male, with a median age of 66 (32-86). Almost all (92.5%) were Caucasian. The primary objective of this pivotal study was to determine the response rate, with secondary objectives to evaluate the safety profile and clinical benefit. The majority of patients reached the target dose regimen of 30 mg three times per week, the proposed regimen for MabCampath. Most patients were treated between 4 and 12 weeks.
The other two studies were non-pivotal, open-label, non-comparative studies. One study had 125 patients with Non-Hodgkins Lymphoma (NHL) including 32 patients with B-CLL who had failed to achieve complete remission or had relapsed after conventional first-line, or subsequent, chemotherapy. The other study had 23 patients with CLL who had failed to achieve complete remission or relapsed from a complete response following various treatment regimens. The objectives of the non-pivotal studies were to evaluate the safety and efficacy in patients with different pathological subtypes of NHL and CLL. Data from the three original studies were limited as few of the patients had B-CLL and various treatment regimens were used.
An additional study (CAm213) followed the three original studies. Study CAm213 was a Phase II, multi-centre, open-label, non-comparative study with 30 patients diagnosed with B-CLL who required treatment and had either failed, were intolerant, or had progressed after treatment with purine analogues. Patients were treated across five study sites in the United Kingdom. Eligible patients were treated with alemtuzumab at a starting dose of 3 mg over 2 hours. The starting dose was increased to 10 mg and then to 30 mg during the first week until the patient tolerated a dose of 30 mg. All subsequent doses were 30 mg intravenous (IV) three times a week for a maximum of 12 weeks. The objectives of this pivotal study were to also determine response and survival rates, to evaluate the safety of alemtuzumab, as well as provide PK data.
Twelve other non-pivotal clinical trials were submitted. These studies were referred to as Phase I or I/II or "pilot" and all of these were also uncontrolled.
3.3.2 Pharmacodynamics
Limited pharmacodynamic studies demonstrated that a reduction in total lymphocyte counts was dose related, and became more significant over time at higher doses. The only exception was in the single dose per week schedule where lymphocyte numbers rebounded between treatments, although not to pre-treatment levels.
With the three doses per week schedule, there was clearance of peripheral lymphocytes and evidence of a reduction in bone marrow lymphocytosis. A general (although not well defined) reduction in lymphadenopathy was apparent. It should be noted that in studies of alemtuzumab in rheumatoid arthritis, there was evidence that lymphocyte infiltration persisted in affected joints, despite alemtuzumab levels that resulted in significant peripheral lymphopenia.
3.3.3 Pharmacokinetics
The PK studies show that trough and peak levels increase with dose, and that there are increasing pre-dose trough levels as treatment progresses.
Only one of the original studies measured and calculated parameters other than peak and trough levels. This study showed the drug exposure parameter (AUC) increasing with dose and with duration of treatment.
Metabolism and excretion studies were not performed. The CD52 positive lymphocyte "compartment" is likely a significant part of the elimination route for alemtuzumab, with the half-life increasing with duration of treatment. PK analysis from study CAm213 demonstrated that the half-life was approximately 9 hours after the initial single dose and was approximately 1 week after 12 weeks of treatment.
3.3.4 Clinical Efficacy
Assessing efficacy was difficult since all studies were uncontrolled. The pivotal study CAm211 and the non-pivotal studies including study CAM 213 are described in section 3.3.1 Clinical Program. With no standard of care for this group of patients, literature reviews were used for comparisons that included patients receiving a variety of salvage regimens. Assessments of efficacy were based on review of literature for other trials of patients with CLL.
In pivotal study CAm211, the efficacy of alemtuzumab was studied in 93 patients with B-CLL who had received an alkylating agent and failed fludarabine therapy. The majority of patients reached the target dose regimen of 30 mg three times per week. Most patients were treated between 4 and 12 weeks.
A complete response (CR) according to conventional clinical assessment occurred in only 2 patients (2.2%) and a partial response (PR) occurred in 29 patients (31.2%). The duration of response was 2.5 months to >22 months, at the time of the last follow-up. There was insufficient data to show whether the two complete responders had a longer duration of response (11.5 months and >21.7 months). As 21 of 51 (67.7%) of responders were still alive at the last follow-up, the median duration of response could not be calculated. The 18 month survival rate was 45.2% (42/93).
Mean survival times after treatment with alemtuzumab in patients with failed purine analogue treatment were better than with other regimens currently used. The duration of response (CR + PR) for alemtuzumab in the updated CAM 211 study was 8.7 months.
Assessment of responders vs. non-responders based on mean baseline CD52 counts, shows that non-responders had higher initial counts: (mean CD52 counts of responders = 20.0 x109/L; non-responders =36.9 x109/L).
In the pivotal CAM 211 study, a clinical benefit analysis was performed, apparently to show improvements that benefited the patient, but which were not apparent when standard response criteria were used. Clinical benefit parameters included specific increases in hemoglobin, reduction in massive splenomegaly and reduction in B symptoms and fatigue. Additional data was requested to try and ensure that the clinical benefit obtained and reported was not at the expense of deterioration in non-responders. The clinical benefit assessments were only applied to responders, in the report. The brief analysis of non-responders compared to responders did show that some of the non-responders obtained benefit. For example, all 17 responders who had B symptoms at enrollment had resolution of those symptoms and 28 of 42 (66.7%) non-responders with B symptoms also had resolution.
Additional analyses were requested to enable assessments of efficacy based on peak drug levels and cumulative doses. Efficacy appears to be unrelated to peak dose, but there is evidence that the response rate increased with increased cumulative dose. Part of this effect may be due to early deaths and patients withdrawing from treatment due to adverse events or disease progression. The percentage of complete and partial responders (CR + PR) compared to all non-responders increased through the cumulative dose cohorts as follows: 0, 22, 25, 25, 46 and 58%. From this additional data, it appears that the current proposed dose regimen is both effective and does not result in additional adverse events.
Study CAm213 provided additional evidence for efficacy. The response was essentially the same as that in study CAm211. Nine (33.3%) of the 27 patients included in the efficacy analysis met the criteria for either a CR (2 patients) or a PR (7 patients). Both CR patients had detectable disease by flow cytometry analysis. Nine (33.3%) met the criteria for stable disease. At the time of the review, there were no dates of disease progression reported for the 9 responding patients with a range of 1.8 to 11.1 months of follow-up. Twenty-four (88.9%) of the 27 patients were alive at the time of the analysis. The median survival time for these patients has not been observed yet, with a range of 1.3 to 13.9 months of follow-up for all patients. In summary, this study does not alter the findings from the pivotal CAm211 study.
3.3.5 Clinical Safety
The safety data provided covered a wide range of clinical studies. The pivotal study CAm211 and the non-pivotal studies including study CAM 213 are described in section 3.3.1 Clinical Program. All studies were uncontrolled, making assessment of safety difficult. There is currently no standard of care for this group of patients. To assess safety, published studies were provided and assessed. The lack of comparative study data severely limited the ability to compare deaths, infections and second malignancies to those for other drug regimens in B-CLL salvage. Also, patients with CLL are prone to severe infections and opportunistic infections, therefore, it is difficult to assess the contribution of alemtuzumab treatment to the incidence of infection. Given the limitations of cohort matching, the data indicates that infectious complications are no worse than with other regimens and death rates are similar. The limited data on second malignancies does not indicate an excess incidence.
Infusion Related Issues
In the pivotal study CAm211, infusion related adverse events were frequent, including rigors 90.3%, fever 84.9%, nausea 52.7%, vomiting 37.6%, and rash 33.3%. Few reactions were severe, with grade 3 or 4 reactions as follows: rigors grade 3, 14.0%, grade 4, 0%; fever grade 3, 17.2%, grade 4, 3.2%; nausea grade 3 or 4, 0%; vomiting grade 3, 1.1%, grade 4, 0%; and rash grade 3 or 4, 0%. Despite the incidence of these adverse events, discontinuations were relatively infrequent with 3 discontinuing due to infusion related events. Compared to some earlier studies with higher single doses, a dose of 30 mg three times per week associated with prophylaxis was tolerable for most patients and symptoms diminished over a course of treatment. There was a small incidence of tumour lysis syndrome. Appropriate warnings and advice on pre-treatment management are included in the Product Monograph. The acute infusion related events are significantly reduced by the use of high-dose steroids, a dose escalation regimen, hydration and the use of allopurinol. Cardiac complications, including cardiac arrest, have not been fully eliminated by these measures. The use of alemtuzumab in patients with pre-existing cardiac disease appears to increase the risk, and in some cases, the risk may outweigh the benefit.
Infections
Infections would be expected to be frequent in patients with advanced CLL and previous immunosuppressive chemotherapy. In the pivotal study CAm211, 51 of the 93 patients (54.8%) experienced at least one infection during the study. Grade 1 or 2 infections occurred in 26 (28%) of the patients and Grade 3 or 4 infections in 25 (26.9%).
In this group of patients, infections are common and opportunistic infections also occur. It is not clear if the incidence of infections such as herpes zoster, cytomegalovirus, pneumocystosis carinii pneumonia and some fungal infections is higher after treatment with alemtuzumab, than with other salvage treatment regimens. Evidence suggests that patients who do receive anti-infective prophylaxis are less likely to have a serious opportunistic infection. Most other infections appear to be manageable, and deaths associated with or attributable to infection may be due as much to the underlying disease as to the use of alemtuzumab and the associated lymphopenia.
The sponsor included adverse event data from a comparative study of alemtuzumab and chlorambucil as first-line treatment in B-CLL. The comparison suggests that infective adverse events are no more frequent with alemtuzumab than with chlorambucil.
Haematological Disorders
Long-term lymphopenia was noted. The duration and recovery of lymphocyte populations showed wide variation. Study data also provided information on total absolute neutrophil count, total CD3+ cells, and the CD3+/CD4+ and CD3+/CD8+ helper and suppressor sub-populations. Both populations were below normal mean levels at 6 months but were above population defined lower limits of the reference ranges. It is likely that the treated patients will have below normal levels of both these populations, and probably other CD52 sub-populations, at 6 months and beyond.
Platelet suppression was more marked with alemtuzumab than with other salvage regimens for CLL. Despite this fact, a significant incidence of hemorrhagic deaths, or serious adverse events did not occur. It was also apparent that platelet counts recovered well in responding patients.
Autoimmune Disorders
The incidence of autoimmune disorders particularly thyroid disorders was increased. Two 'special case' safety issues occurred: the reactivation of symptoms associated with old, quiescent lesions in Multiple Sclerosis (MS), and a significant incidence of thyroid disease, predominantly in patients with MS. Warnings and advice on pre-treatment are included in the Product Monograph.
It is clear that thyroid disease occurred predominantly, but not exclusively, in patients with MS. This event may have been due to an inherited susceptibility in these patients. Thyroid disease is an autoimmune thyroiditis, but this may manifest, rarely, as hypothyroidism. This adverse event has only been reported in one patient in all the B-CLL studies. The Product Monograph includes information on this issue indicating that patients with other auto-immune disorders may be at risk and should be monitored. In the cases of Graves' disease followed-up by the sponsor, about one-third resolved spontaneously following a period of anti-thyroid medication, but two-thirds required definitive thyroid ablative therapy, and one patient experienced serious opthalmopathy.
The incidence of anti-alemtuzumab antibodies was low in patients receiving alemtuzumab by intravenous infusion and no clinical sequelae were identified. A small number of patients who had pre-existing antibodies were re-treated and no adverse events were reported.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Submitted data provided evidence for efficacy in patients with B-CLL who have failed treatment with alkylating agents and fludarabine. Treatment with MabCampath resulted in longer median survival times than other regimens currently in use. In addition, death rates appeared to be lower and quality of life improved. There is currently no 'standard of care' for patients who have failed first and second line treatment for B-CLL. Therefore a treatment which offers a proportion of patients, including those who do not attain traditional 'clinical' responses, a prolongation of life, associated with some improvements in quality of life, is suitable for authorization.
The adverse event profile is acceptable, particularly when considered in the context of a lack of efficacious alternatives. Appropriate warnings and advice are in the Product Monograph to ensure that appropriate prophylactic measures are taken to reduce serious adverse events, such as tumour lysis syndrome, opportunistic and other serious infections and severe, early, infusion related symptoms such as rigors. Warnings have been enhanced, based on safety update reports and the reported incidence of opportunistic infections, autoimmune disorders, and more serious adverse events associated with infusion.
The dosage regimen proposed, with an escalating dose based on tolerability, followed by a three times per week regimen at 30 mg per dose, IV, is satisfactory. The typical cumulative dose over a 12-week schedule is not associated with any significantly increased incidence of adverse events, compared to shorter treatment periods. Warnings regarding higher single doses and particularly, higher than recommended starting doses are in place.
The benefit of MabCampath for patients with failed prior first-line treatment and failed fludarabine treatment is clearly greater than the risks associated with the drug.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of MabCampath is favourable for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. 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: Mabcampath®
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2001-08-08 |
| Rejection issued by the Director of BBR: | 2001-09-13 |
| Submission filed: | 2005-05-06 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2001-12-21 |
| Response filed: | 2002-02-01 |
| Screening Acceptance Letter issued: | 2002-02-15 |
| Review 1 | |
| Quality Evaluation complete: | 2004-12-23 |
| Clinical Evaluation complete: | 2005-11-25 |
| Labelling Review complete: | 2005-11-24 |
| NOC issued by Director General: | 2005-11-30 |